
==== Front
J Transl Med
J Transl Med
Journal of Translational Medicine
1479-5876
BioMed Central London

39218900
5451
10.1186/s12967-024-05451-w
Review
Tailoring of apoptotic bodies for diagnostic and therapeutic applications:advances, challenges, and prospects
Miao Xiaoyu 1
Wu Xiaojin 1
You Wenran 1
He Kaini 1
Chen Changzhong 1
Pathak Janak Lal j.pathak@gzhmu.edu.cn

1
http://orcid.org/0000-0003-4272-0818
Zhang Qing zhangqing@gzhmu.edu.cn

12
1 https://ror.org/00zat6v61 grid.410737.6 0000 0000 8653 1072 School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, 510182 China
2 https://ror.org/008xxew50 grid.12380.38 0000 0004 1754 9227 Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands
1 9 2024
1 9 2024
2024
22 81016 2 2024
28 6 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Apoptotic bodies (ABs) are extracellular vesicles released during apoptosis and possess diverse biological activities. Initially, ABs were regarded as garbage bags with the main function of apoptotic cell clearance. Recent research has found that ABs carry and deliver various biological agents and are taken by surrounding and distant cells, affecting cell functions and behavior. ABs-mediated intercellular communications are involved in various physiological processes including anti-inflammation and tissue regeneration as well as the pathogenesis of a variety of diseases including cancer, cardiovascular diseases, neurodegeneration, and inflammatory diseases. ABs in biological fluids can be used as a window of altered cellular and tissue states which can be applied in the diagnosis and prognosis of various diseases. The structural and constituent versatility of ABs provides flexibility for tailoring ABs according to disease diagnostic and therapeutic needs. An in-depth understanding of ABs’ constituents and biological functions is mandatory for the effective tailoring of ABs including modification of bio membrane and cargo constituents. ABs’ tailoring approaches including physical, chemical, biological, and genetic have been proposed for bench-to-bed translation in disease diagnosis, prognosis, and therapy. This review summarizes the updates on ABs tailoring approaches, discusses the existing challenges, and speculates the prospects for effective diagnostic and therapeutic applications.

Highlights

Apoptotic bodies (ABs), a type of cellular waste product discovered as a biomaterial with therapeutic potential

ABs mediated intercellular communication, including the transmission of biological signals and biological substances

Apoptotic bodies exhibit significant research and application potential in the prevention, diagnosis, and treatment of diseases.

The functionality of apoptotic bodies can be enhanced through drug loading, surface modification, and biomimetic preparation.

Keywords

Apoptotic bodies
Engineering method
Biology function
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 32301129 31801152 Zhang Qing Science and Technology Planning Projects of Guangzhou City, China202201020203 202201020117 Zhang Qing Guangzhou Science and Technology Plan Project, China2023B03J1240 Zhang Qing Special projects in key fields of Guangdong Colleges and Universities, China2021ZDZX2058 Zhang Qing Undergraduate Teaching Quality and Teaching Reform Engineering Projects of Guangzhou Medical University2021-28-2 2021-159-48 2022-124-1 Zhang Qing issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Apoptotic bodies (ABs) are small membrane-bound vesicles derived from apoptotic cells, which have long been recognized for their critical role in the maintenance of tissue homeostasis and the elimination of unwanted or damaged cells. ABs are formed by programmed cell death, namely apoptosis, which is essential for the growth, development, tissue renewal, and homeostasis of organisms [1, 2]. Unlike necrosis, which is a form of cell death that releases cellular contents and triggers an inflammatory response, apoptosis is a controlled process that eliminates individual cells without triggering inflammation or damage to the surrounding tissues [3]. ABs were first discovered by researchers in 1962–1964 [4]. Initially, ABs were considered cellular waste produced by cell damage, without any specific physiological function [5]. Studies in the last decade found the diagnostic and therapeutic potential of ABs. Recent studies have shown that ABs are not only involved in the clearance of apoptotic cells but also have unique biological properties that make ABs ideal candidates for disease diagnosis and therapy [2, 6–12]. ABs carry diverse cargo such as proteins, metabolites, and nucleic acids that can be transferred to adjacent cells, thereby regulating cellular function, or signaling pathways to promote healing and tissue regeneration [7, 13–21]. Moreover, ABs from specific cell types have been shown to alleviate inflammation [15, 22], disease progression [9, 10], and tissue injury [11, 23], suggesting their potential utility in disease management. Advancements in proteomics, transcriptomics, and cellular engineering have made it possible to identify novel molecules and pathways involved in ABs biology, construct ABs with good biocompatibility and diverse functions, and expand their application in disease diagnosis and therapy [24]. Although ABs have great application potential in disease diagnosis and treatment, the exploitation of ABs is still in its infancy, and several challenges need to be addressed, including the optimization of ABs isolation and characterization techniques, the standardization of experimental protocols, and the development of innovative therapeutic strategies based on ABs tailoring.

Based on the abovementioned facts, this review aims to provide readers with a comprehensive understanding of ABs’ tailoring for use in disease diagnosis and therapy. The review begins by presenting an overview of ABs biology, including their origin, occurrence, and recent developments. Then, it explores the biological functions and potential applications of ABs in disease diagnosis and therapy followed by a discussion on the typing, induction, and engineering modification of ABs. Finally, the review summarizes the advances in ABs-related research and prospects for future research in the field of ABs’ tailoring for application in disease diagnosis and therapy. The information presented in this review article will be valuable to researchers and clinicians working in the field of AB-based disease diagnosis, management, and therapy.

Methods

We conducted literature searches on three databases, including Web of Science, PubMed, and Scopus in January 2023. The search period ranged from 1st January 2010 to 1st January 2023. The search strategies used were as follows. Web of Science: (TS = (“apoptotic bodies*” OR “apoptotic body*” OR “extracellular vesicle*”)); PubMed: (apoptotic bodies* OR apoptotic body* OR extracellular vesicle*); and Scopus: TITLE-ABS-KEY (“apoptotic bodies*” OR “apoptotic body*” OR “extracellular vesicle*”).We also conducted a manual search by reviewing the reference lists of key published articles to identify additional eligible studies.

The included articles were: (1) peer-reviewed original research article or review article; (2) published in English. The excluded articles were: (1) letter, commentary, proceeding paper, conference abstract, meta-analysis, patent, case report, editorial, book chapter, non-peer-reviewed publication (including preprint), or retracted publication; (2) published in languages other than English.

The biological features of ABs

Based on size and biogenesis, extracellular vesicles (EVs) can be classified into three subtypes: exosomes (30–150 nm), microvesicles (50–1000 nm), and ABs (50–5000 nm) [25, 26]. The distinctions among these EVs are listed in Table 1. Different from exosomes and microvesicles, ABs are membrane-bound vesicles that are released by dying cells in the final stage of apoptosis [27]. This controlled procedure consists of three steps (Fig. 1)[28]. Firstly, apoptotic membrane blebbing is a crucial step in ABs formation mediated by cysteine protease 3 (caspase-3) phosphorylation and activation of protein kinases, particularly Rho-associated protein kinase 1 (ROCK1) [29, 30]. Other kinases such as myosin light chain kinase (MLCK), Lim domain kinase 1 (LIMK1), and p21-activated kinase (PAK2) are non-essential kinases but may also be involved in apoptotic membrane blebbing [29]. These kinases contribute to actomyosin cortex contraction, leading to the generation of hydrostatic pressure and the entry of intracellular fluid. These processes cause the separated membrane to expand [30, 31]. After expansion, the actin and myosin II gathered in the vesicles to form a cortex attached to the plasma membrane, causing the expansion rate to slow down [30]. The contraction and assembly of this cortex ultimately result in the formation of plasma membrane vesicles [30]. Apoptotic membrane protrusions generated by apoptotic cells are methods independent of apoptotic membrane blebbing to form ABs [32, 33]. There are three kinds of membrane protrusions: microtubule spikes inhibited by pan-catenin 1 (PANX1) channel and activated by vesicle transport [34, 35], beaded protrusions activated by transmembrane receptor plexus B2 (PlexB2) and microtubules [33, 35], and PANX1-inhibited apoptopodia [35, 36]. Finally, the fragmentation of membrane protrusion forms independent ABs [32, 33].Table 1 Comparisons of ABs, exosomes, and microvesicles’ biological properties

	ABs	Exosomes	Microvesicles	Refs.	
Size (diameter)	50–5000 nm	30–150 nm	50–1000 nm	[25, 26]	
Morphology	Heterogeneous	Cup-shaped	Various shapes	[25, 26]	
Lipid composition	High PS exposure and cholesterol	LBPA, low PS exposure, cholesterol, ceramide, contains lipid rafts, and sphingomyelin	High PS exposure and cholesterol	[25, 26]	
Biogenesis mechanism	Cell shrinkage and death	Exocytosis of intracellular multivesicular bodies	Plasma membrane shedding	[51–53]	
Mode of extracellular release	Regulated	Constitutive and regulated	Regulated	[51–53]	
Characteristic biomarkers	PTPRC, Caspase-3, C3b, C1q, CRT, TSP, H2AX, LFA-1, CD45, and PS	Alix, TSG101, HSP70, HSP90, CD9, CD63, CD81, Annexin I, Annexin II, Annexin V, Flotllin-1, Flotillin-2, ICAM, TSP1, and periostin	Selectins, integrins, CD40, metalloproteinases, and PS	[33, 53, 54]	
Content	Protein, nucleic acids (DNA, miRNA, mRNA, non-coding RNA), lipid, metabolite, residual cytoplasm, and organelles	Protein, nucleic acids (DNA, miRNA, mRNA), lipid, and metabolite	Protein, nucleic acids (DNA, miRNA, mRNA), lipid, and metabolite	[25, 26]	
ABs apoptotic bodies, PS phosphatidylserine, LSBPA 2,2′-lysobisphosphatidic acid, PTPRC protein tyrosine phosphatase receptor C, Caspase-3 cysteine protease 3, CRT calreticulin, TSP thrombospondin, LFA-1 lymphocyte function-associated antigen 1, TSG tumor susceptibility gene 101, heat shock protein 70, ICAM intercellular adhesion molecules, TSP1 thrombospondin 1

Fig. 1 Illustration of the mechanism of ABs biogenesis. (I) Cell membrane blebbing is activated by active cysteine protease 3 to activate ROCK1, PAK2, MLCK, and LIMK1, leading to actomyosin contraction. (II) Apoptotic membrane protrusion formation through the PANX1 channels and vesicle transport, resulting in the formation of microtubule spikes, bead-like protrusions, and apoptopodia. (III) Fragmentation to form ABs. LIMK1 lim domain kinase 1, MLCK myosin light chain kinase, PAK2 p21-activated kinase, PANX1 pan-catenin 1, PlexB2 plexus B2, ROCK1 Rho-associated protein kinase 1. Created with BioRender.com

As cell debris, ABs inherit cellular components and surface markers from parent cells (Fig. 2) [37]. The content of ABs can be utilized for their isolation, characterization, and diagnostic and therapeutic applications. Proteins and non-protein surface markers can be utilized in ABs isolation and biological signals. Protein markers including thrombospondin (TSP) [10, 14], complement proteins C3b and C1q [38], leukocyte common antigen protein tyrosine phosphatase receptor C (PTPRC) [38], integrin lymphocyte function-associated antigen 1 (LFA-1) [38], caspase-3 [8, 39], calreticulin (CRT) [40], histone H2AX [41], and leukocyte common antigen (LCA) such as CD45 [38] are commonly utilized ABs surface markers. One of the signs of ABs is to contain nuclear proteins, which differs from other EVs [42]. Phosphatidylserine (PS) is a non-protein marker of ABs. PS is a component of cell membranes which is normally located under the cell membrane in normal cells, and during apoptosis, enzymes catalyze the externalization of PS [19, 43–48].Fig. 2 The surface markers and bioactive cargos of ABs. CRT calreticulin, PS phosphatidylserine, PTPRC protein tyrosine phosphatase receptor C, TSP thrombospondin, LFA-1 lymphocyte function-associated antigen 1

Credited with unique biological properties, ABs exhibit unrivaled advantages in target accuracy, therapeutic effectiveness, and safety compared to other EV-based approaches. First, benefiting from the specific recognition and efferocytosis mechanisms including “find-me” and “eat-me” signals, ABs exhibit fewer off-target effects and more potent responses compared to EVs derived from non-apoptotic cells. Furthermore, among all osteoclast-derived EVs, ABs show the highest level of nuclear factor kappa B (RANK), granting them the greatest osteogenic potency [19]. Additionally, inherited from parent cells, ABs do not contain autoantibodies [49], which offers advantages in regenerative therapy, especially in organ transplantation, since they do not induce inflammatory responses or graft rejection as observed in other EVs.

Although various biological features make ABs a powerful candidate in disease diagnosis and therapy, the complexity of their constituents causes ambiguity in characterization [50]. Therefore, further improvement in ABs’ isolation and characterization is required to fully utilize their superior potential in clinical translation.

Isolation and characterization of ABs

During apoptosis, cells form ABs through various means, which differ in composition, size, and other biology properties [32]. Therefore, accurate isolation and characterization of various ABs is essential for their effective application in disease diagnosis and therapy. Among the most used methods for ABs isolation are differential centrifugation, filtration, and fluorescence-activated cell sorting (FACS). We summarize these three separation methods in detail below, including their separation principles, main applications, and advantages as well as disadvantages (Table 2). The characterization methods of ABs are summarized based on their features including specific markers and physicochemical properties (Table 3). These mainly include flow cytometry (FCM), immunohistochemistry, low-temperature transmission electron microscopy (Cryo-TEM), nanoparticle tracking technology (NTA), and nanopore technology [55–58].Table 2 The isolation methods of ABs

Method	Principle	Application	Advantages	Disadvantages	Refs.	
Differential centrifugation	Difference between the density of ABs and other components in the mixture	ABs extraction of single-cell type	High purity (~ 83%), quick (30 min), and relatively higher yield	Low specificity toward biomarkers	[59–61]	
Filtering method	Size of ABs (1–5 μm)	Combination with differential centrifugation	Simple operation	Low purity and yield	[14, 60, 62–64]	
Flow cytometry	The relative size, particle size, and specific biomarkers of ABs	ABs extraction of multiple cell types	High purity (~ 99%)	Complex procedure and time-consuming	[59, 65]	

Table 3 The characterization methods of ABs

Principle	Method	Application	Advantages	Disadvantages	Refs.	
Biomarkers	FCM	PS measurement	Most commonly used	Complex procedure and lack of specific markers	[37]	
Immunohistochemistry	H2AX characterization	High specificity	______	[41]	
Physicochemical properties	Cryo-TEM	Determination of particle size and shape	High resolution	Use of harsh conditions and hexagon/glassy ice-polluted images	[55, 56]	
NTA	Analysis of the number and size of ABs	______	______	[57]	
Nanopore technology	Gene sequencing, determination of particle size, and identification of cell types specific ABs	Simple procedure	Time-consuming	[58]	
FCM:flow cytometry, PS:phosphatidylserine, Cryo-TEM low-temperature transmission electron microscopy, NTA nanoparticle tracking technology

There is currently no standardized method for the isolation and characterization of each subpopulation of ABs, primarily due to a lack of specific markers and overlaps in physicochemical properties. Careful selection of suitable techniques for ABs’ isolation and characterization based on their application objectives is crucial. Most importantly, further exploration into the isolation and characterization of ABs is urgently required to fully understand the complexity of apoptosis within biological systems and provide a basis for future research on developing ABs as diagnostic and therapeutic targets.

The sources of ABs for diagnostic and therapeutic applications

ABs come from a wide variety of sources, including cells, body fluids, and tissues (Fig. 3). ABs from different sources have different functions and potential diagnostic and therapeutic applications. ABs are derived from a variety of cellular sources and exhibit distinct functions. Osteoclast-derived ABs stimulate osteogenesis and mitigate osteoporosis [9, 66]. MSC-derived ABs possess anti-inflammatory properties and facilitate tissue healing [14]. Immune cell-derived ABs exhibit remarkable anti-inflammatory properties, making them promising candidates for treating inflammatory disorders [38, 67, 68]. Endothelial cell-derived ABs induce angiogenesis and play a crucial role in wound repair [11, 23]. Cardiomyocyte-derived ABs promote myocardial regeneration and enhance myocardial infarction (MI) recovery. Recent studies demonstrated that ABs extracted from rat cardiomyocytes enhanced the proliferation and differentiation of cardiac stem cells, thereby improving myocardial contractility in rats [69, 70]. Cancer cell-derived ABs have the potential to penetrate the blood–brain barrier (BBB), offering possibilities for targeted drug delivery in the brain [71–74]. In addition, like other EVs, ABs derived from cells have the advantages of high purity and good stability [6, 14]. The low production of ABs from cells limits their large-scale development and utilization. However, with the breakthrough of rapid cell expansion technology in recent years, especially 3D cell culture technology [75–78], these limitations are radially overcome.Fig. 3 The sources and induction methods of ABs. ABs can be derived from cells, body fluids, and tissues. The in vitro induction methods of ABs to improve the yield. Created with BioRender.com

Unlike cell-derived ABs with high purity and stable performance, body fluid and tissue-derived ABs are more complex, contain more disease information, and change with patients' physical conditions. Therefore, body fluid-derived ABs have high diagnostic and prognostic values. The main sources of ABs from body fluids include blood, cerebrospinal fluid, urine, and other sources. Blood ABs are readily available and can be used as a non-invasive way to monitor disease activity and prognosis in various pathological conditions including cerebrovascular and neurodegenerative [79]. Urinary ABs can diagnose kidney disease and are expected to be used in clinical trials [80]. Cerebrospinal fluid-derived ABs currently do not accurately reflect the degree of central nervous system disorder, and further research is needed in this direction [81]. Body fluid-derived ABs can be extracted quickly, which is conducive to clinical testing. Compared to ABs obtained from cells or body fluids, ABs isolated directly from tissues are tissue-specific and accurately reflect the tissue microenvironment. For example, the ABs index of osteosarcoma tissue combined with serum alkaline phosphatase is suggested as an effective indicator of malignancy degree and prognosis that assists in monitoring therapeutic effect [82]. Tissue-derived ABs have tissue specificity, which is more beneficial to disease diagnosis and personalized treatment.

The biological functions of ABs

In addition to a comprehensive understanding of various sources, clarifying the biological function of ABs is also the basis for their application. ABs serve as a means of intercellular communication since nearly all eukaryotic cells can release ABs that act on adjacent and distant cells [83]. Due to the complex biological information and components derived from dead cells present in ABs, they can elicit intricate and diverse effects on receiver cells [13, 14, 21]. However, there remains a lack of systematic elaboration on the biological function of ABs. This chapter aims to review the biological functions of ABs and explore their potential application prospects, including biological information transmission, biomolecule transport, and regulation of autophagy, proliferation, differentiation, and immunity.

ABs-mediated intercellular communication

ABs transmit intercellular signals and biomolecules to detect and remove necrotic cell debris (Fig. 4), which is essential for maintaining tissue homeostasis [27]. Apoptotic substances that cannot be effectively removed can induce secondary necrosis and inflammation, leading to autoimmune diseases such as systemic lupus erythematosus or other immune-related diseases [84, 85]. Therefore, understanding the intercellular communication functions of ABs, as well as their regulation mechanisms, is of great significance for the prevention and treatment of immune-related diseases. Further research on the regulatory mechanisms and interactions of these intercellular communications will guide to development of new therapeutic strategies to promote tissue regeneration and repair. ABs are involved in intercellular communication mainly via “find-me” and “eat-me” signals [86–92].Fig. 4 Illustration of ABs involved in intercellular communication. ABs can harbor “find-me” signals to attract phagocytic cells, as well as “eat-me” signals to promote uptake by phagocytes. ABs transport biomolecules (e.g., DNA, RNA, protein, and metabolite) to neighboring cells via endocytosis and membrane fusion. BAI1 brain-specific angiogenesis inhibitor 1, MerTK tyrosine-protein kinase Mer, TIM T cell immunoglobulin mucin proteins. Created with BioRender.com

The transmission of biological signals including “find-me” and “eat-me” signals plays a crucial role in apoptotic cell clearance [27, 93]. Apoptotic cells possess substances known as “find-me” signals to attract phagocytes, followed by the quick identification and engulfment of apoptotic substances by phagocytes via “eat-me” signals. It has been observed that ABs derived from apoptotic cells also possess the ability to recruit phagocytes [94–96]. The “find-me” signals of ABs are PS-bound chemokines, which are released by apoptotic cells and can selectively bind to PS exposed on the surface membrane of ABs. This binding activates chemokine receptors on phagocytes via chemokines, thereby inducing phagocyte migration [87]. Subsequently, “eat-me” signals exposed on the membrane surface of ABs including PS [88–92] and CRT [40] start to exert their functions. The recognition of PS is crucial for the efficient clearance of apoptotic substances, therefore resulting in the maintenance of tissue homeostasis and prevention of autoimmunity. This process includes multiple receptors such as T cell immunoglobulin mucin proteins (TIM-1, TIM-3, TIM-4), brain-specific angiogenesis inhibitor 1 (BAI1), tyrosine-protein kinase Mer (MerTK), stabilin 1 and 2 [86, 88–92]. PS exposure on the membrane can also be recognized by integrin αvβ3 to repair cell damage and improve the osteogenic and adipogenic differentiation ability of BMSCs [14]. In addition, CRT‐mediated efferocytosis of MSC‐derived ABs by macrophages reduces liver macrophage infiltration and pro-inflammatory transformation, which ameliorates T2D [40]. Although multiple ABs’ surface markers have been identified, further studies are needed to determine whether they can participate in cell clearance as biological signals.

During the process of apoptosis, membrane foaming and protrusion formation facilitate the redistribution of cellular components into ABs [33]. Different formation processes affect the biomolecules carried by ABs. Beaded protrusions, for instance, contribute to the generation of ABs that lack nuclear components [33]. In addition, the cleavage and activation of caspase-3 during apoptosis can affect more than 280 downstream targets, and the resulting unique cytokines, microRNAs (miRNAs), and mitotic proteins are packaged into ABs and then transported to adjacent cells [18, 97]. Subsequently, ABs act as intercellular carriers of biomolecules. ABs mainly act on receptor cells via endocytosis and membrane fusion[17–20]. ABs can transfer DNA [16, 98], RNA [14, 15] mainly miRNA including miR-328-3p, -21-5p, -126, -155, -221 and -222 [23, 67], proteins including wnt8a, insulin growth factor 2 mRNA-binding protein 3 (IGF2BP3), ring finger protein 146 (RNF146), platelet-derived growth factor-BB (PDGF-BB), receptor activator of RANK and interleukin-1a (IL-1a) [17–20], metabolites (pyridoxine and kynurenine) [21], and other signaling molecules into the target cells (Figs. 2 and 4). ABs transport genomic DNA to adjacent cells to achieve horizontal gene transfer between different cell types, leading to the occurrence of disease [16]. In the mouse xenobiotic model, ABs have been reported to be involved in regulating the circulation of distal cells, suggesting that the reuse of ABs components may be a common biological activity in the body [14]. In addition to biomolecules, ABs can also be used as carriers for transferring influenza A virus IAV to adjacent cells to achieve virus transmission between cells [99]. Through the transport of these functional biomolecules, ABs transmit information between cells and mediate specific biological effects.

ABs regulate cellular function

Cellular function is regulated by complex molecular mechanisms that allow cells to respond to their environment and maintain homeostasis [100]. These mechanisms involve a series of signaling pathways that regulate gene expression, protein synthesis, and cellular metabolism. ABs themselves and the biological information they carry participate in a cascade of intracellular signaling events that ultimately lead to changes in gene expression and protein synthesis. Therefore, ABs play a complex and dynamic role in the regulation of cell autophagy, proliferation, and differentiation, as well as immune responses, allowing organisms to adapt and respond to changing conditions in their environment [14, 15].

ABs regulate cell autophagy

Autophagy is a lysosomal-mediated catabolic process that maintains cellular homeostasis by processing damaged, nonfunctional, or unnecessary proteins and organelles [101]. Recent studies have revealed that ABs derived from MSCs serve the function of upregulating autophagy in receptor epithelial cells [8]. Specifically, in ECs, ABs activate lysosomal function and promote the expression of transcription factor EB (TFEB), which is the master regulator of lysosomal biogenesis and autophagy [102]. The increased presence of TFEB enhances the expression of autophagy-related genes and proteins including BECN1, LC3, and ATG5 in ECs following MI. This activated autophagy leads to increased nitric oxide (NO) production through the vascular endothelial growth factor (VEGF) signaling pathway, ultimately promoting angiogenesis in vivo. Consequently, this promotes recovery of myocardial function and improves cardiac infarction [8]. There is a complex relationship between apoptosis and autophagy, and the relatively stable state of the two is of great significance for maintaining the physiological function of cells [103]. The imbalance between apoptosis and autophagy can lead to the development of cardiovascular diseases (CVD), cancer, and brain injuries [104–106]. The critical role of ABs in regulating autophagy is expected to be involved in the regulation of these diseases.

ABs regulate cell proliferation and differentiation

Cell proliferation is the process by which cells divide and replenish aging or dead cells in vivo, which is essential for tissue regeneration [107–110]. ABs have been shown to regulate cell proliferation (Fig. 5) [17, 20]. Specifically, ABs induced by the anticancer drug cisplatin exert a proliferative effect on human renal proximal tubular HK-2 cells and induce apoptosis, subsequently giving rise to second-generation Abs [17]. Interestingly, these second-generation ABs mediate the opposite effect through the same pathway and stimulate cell proliferation [17]. Furthermore, ABs derived from tenocytes stimulate the proliferation and migration of tenocytes and bone marrow mesenchymal stem cells (BMSCs) and induce these cells to synthesize more transforming growth factor-β (TGF-β) and types I and III collagen [111]. Since TGF-β controls cell proliferation and migration and collagen is the main component of tendons, ABs promoting the high expression of the protein and collagen ultimately enhance tendon healing [111–113]. In addition, the positive role of ABs in the proliferation of fibroblasts and endothelial progenitor cells (EPCs) as well as cardiac stem cells (CSCs) is conducive to tissue regeneration, promoting angiogenesis and myocardial repair, respectively [39, 70]. However, not all proliferation promoted by ABs is benign cell growth, there is also a malignant tumor-promoting effect. ABs from tumor cells enhance programmed cell death ligand 1 (PD-L1) upregulation on GATA6 large peritoneal macrophages (GLPMs), which block cytotoxic activity of PD-1-expressing CD8+ T cells. and indirectly protect tumor cells [114]. ABs induced by Cytosine arabinoside (Ara-C) carry IGF2BP3 to promote blood cell proliferation and reduce apoptosis by regulating phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathways [20]. Since IGF2BP3 is a potential oncogene that can induce tumorigenesis [115], ABs carrying IGF2BP3 promote oncoprotein growth in receptor cells and play a tumor-promoting role [20]. Moreover, ABs derived from macrophages exhibit the ability to suppress the expression of cyclin-dependent kinase inhibitor 1B (CDKN1B) in lung epithelial cells via miR-221 and -222, subsequently promoting epithelial cell growth, and contributing to epithelium integrity [67]. Considering that CDKN1B is a tumor suppressor [116], the inhibitory effect of ABs on CDKN1B may lead to unregulated tumor-like proliferation of epithelial cells and lung epithelium integrity [67]. In summary, on one hand, ABs promote the benign proliferation of stem cells, thereby promoting cardiovascular, tendon, and lung epithelium regeneration [111, 117], on another hand, ABs play a role in promoting abnormal cell proliferation such as tumors [20, 114].Fig. 5 Reported mechanisms of ABs regulating cell proliferation. A ABs promoted receptor cell proliferation through COX2/IPGE2/EP signaling pathway[17]. B ABs activated the Wnt/β-catenin pathway through the signal protein Wnt8a to promote cell proliferation [18]. C ABs induce proliferation of the recipient cells via miR-221/222 [67]. D ABs promoted cell proliferation by releasing IGF2BP3 and activating PI3K/AKT and P42/44 MAPK pathways in receptor cells [20]. IGF2BP3 insulin growth factor 2 mRNA-binding protein 3. Created with BioRender.com

Cell differentiation is a process whereby cells of the same types undergo morphological structure and physiological function changes, leading to the formation of distinct cell groups essential for organismal function [107, 118, 119]. Growing pieces of evidence suggest that ABs can regulate cell differentiation. The regulatory effects of ABs on cell differentiation can be categorized based on the specific direction of differentiation, including osteogenesis [14, 120], angiogenesis [7], cardiac differentiation [69, 70], and adipogenesis [14]. The regulatory mechanisms are summarized in the following (Fig. 6).Fig. 6 Reported mechanisms of ABs regulating cell differentiation. A ABs promote receptor cell differentiation through the PI3K/AKT/mTOR signaling pathway [7, 9, 19]. B ABs carrying PDGF-BB may activate PI3K/AKT pathways to promote cell differentiation [7]. C ABs inhibit the SMAD2 signaling pathway via miR-155 for promoting cell differentiation [68]. D RNF146 and miR-328-3p in ABs inhibit the expression of gene Axin1 to activate the Wnt/β-catenin pathway, thereby promoting cell differentiation [14]. PDGF-BB platelet-derived growth factor-BB, SMAD2 drosophila mothers against decapentaplegic protein 2, RNF146 ring finger protein 146. Created with BioRender.com

Osteogenic differentiation is a key step in bone formation, wherein BMSCs differentiate into various bone cell types, including osteogenic precursor cells, mature bone cells, and terminal bone cells. This complex process involves multicellular signal delivery [121]. In recent years, many studies have revealed the regulatory mechanism of ABs in regulating osteogenic differentiation. For example, mOC-ABs induce the osteogenic differentiation of BMSCs and preosteoblasts through reverse signaling of the receptor activator of nuclear factor kappa B ligand (RANKL) mediated by RANK [7, 9, 19]. RANKL reverse signaling activates the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin/s6 kinase (PI3K/AKT/mTOR/S6K) signaling pathway related to osteogenesis, thereby promoting osteogenic differentiation [122]. MSCs can repeatedly use miR-328-3p and ubiquitin ligase RNF146 in ABs to inhibit the expression of Axin1, thereby activating the Wnt/β-catenin pathway, which improves the osteogenic and adipogenic abilities of MSCs [14, 120]. In addition, ABs can also inhibit bone formation. Osteocyte-derived ABs stimulate the release of tumor necrosis factor-α (TNF-α) by osteoclast precursors, which plays a key role in osteoclastogenesis and bone resorption [48, 123, 124]. MiR-155 inhibits osteogenesis but promotes adipogenesis of MSCs cultured with macrophage-derived ABs via the drosophila mothers against the decapentaplegic protein 2 (SMAD2) signaling pathway [68].

It has been reported that ABs can directly promote angiogenesis or indirectly promote vascular differentiation by recruiting endothelial stem cells to damaged vascular tissues [7, 39, 70]. ABs derived from fibroblasts and human umbilical vein endothelial cells (HUVECs) initiate the differentiation of endothelial cells (ECs) and promote angiogenesis [70, 117]. POC-ABs induce the differentiation of ECs via PDGF-BB and PI3K/AKT pathways to exert vascularization effects [7]. ABs can also indirectly exert vascularization by recruiting stem cells. ABs derived from ECs have been shown to carry miR-126 to ECs, which inhibits the function of regulator of G protein signaling 16 (RGS 16) in receptor cells, and promotes the expression of CXC chemokine CXCL12 via its receptor CXCR4 [23]. CXCL12 then recruits CD31+ ECs from bone marrow to blood vessels to reduce apoptosis, which promotes atherosclerosis protection and vascular endothelial repair in mouse models. Moreover, ABs derived from retinal microvascular endothelial cells can mediate ECs releasing of angiogenic cytokines and chemokines, and induce the expression of adhesion molecules, such as intercellular adhesion molecules (ICAM), vascular cell adhesion molecules, and endothelial cell leukocyte adhesion molecule-I to recruit EPCs to damaged blood vessels and repair damaged endothelium [11]. In addition, ABs can indirectly enhance fibroblast migration by inducing macrophage M2 polarization, thus promoting angiogenesis and wound repair [39].

Myocardial regeneration refers to the process by which non-cardiac cells in the heart are converted into functioning cardiac muscle cells, called cardiomyocytes, to repair damaged or diseased heart tissue. Cardiomyocytes-derived ABs have shown the ability to stimulate the myocardial differentiation of CSCs [69, 70]. In summary, ABs have been reported to have multiple effects in regulating cell differentiation, particularly promoting osteogenesis, angiogenesis, cardiomyogenesis, and adipogenesis by the activation of specific signal pathways.

ABs mediated immune response

ABs not only participate in the regulation of autophagy and differentiation but also play a role in immune system regulation (Fig. 7). ABs can treat diseases or restore damaged functions by modulating the immune microenvironment of the body or specific diseases [15, 22, 39, 125]. Macrophages play a crucial role in the innate immune system and are important in immune regulation. Anti-inflammatory M2 macrophages are considered subtypes that inhibit osteoclast differentiation and promote bone regeneration. ABs can induce macrophages to polarize towards the anti-inflammatory M2 phenotype, mainly via the reduced expression of pro-inflammatory factors such as TNF-α, IL-6, and IL-12, and the increased expression of anti-inflammatory factors such as TGF-β and IL-10, which helps mitigate inflammatory responses [15, 39, 125]. In addition, miR-21-5p abundantly expressed in ABs targets Kruppel-like factor 6 to induce M2 polarization [15, 22].Fig. 7 ABs mediated immune response. Anti-inflammatory effect: ABs reduce the expression of pro-inflammatory factors (TNF-α, IL-6, and IL-12) in receptor macrophages, and increase the expression of anti-inflammatory factors (TGF-β and IL-10), inducing M2 macrophage polarization. Pro-inflammatory effect: ABs carry IL-1α, which can induce high expression of neutrophil chemokines and promote neutrophil infiltration to drive sterile inflammation after injection into the peritoneal cavity of mice. Created with BioRender.com

Interestingly, ABs have also been reported to exhibit pro-inflammatory effects (Fig. 7). ABs derived from ECs containing pro-inflammatory factor IL-1α induce high expression of neutrophil chemokines such as monocyte chemoattractant protein-1 and IL-8 promoting the infiltration of neutrophils and driving sterile inflammation upon injection into the peritoneal cavity of mice, leading to tissue damage and aggravating diseases [126, 127]. To sum up, ABs mainly exert anti-inflammatory effects to promote wound healing, but it has also been reported to promote inflammation and thus play a dual role in inflammation regulation.

The application of ABs in disease diagnosis and therapy

Based on the information covered in the previous chapter, ABs possess significant functions such as participating in cell communication and transmitting biological substances. These characteristics make ABs highly promising in disease diagnosis and treatment. In this chapter, we will provide a detailed overview of the recent advancements in the application of ABs in disease diagnosis and treatment. We will explore specific cases and discuss how ABs have been utilized in various medical fields, including but not limited to diabetes prevention, immune disease diagnosis, bone, skin, tumor, immune disease, and cardiovascular disease treatment [128–136]. By highlighting recent research and advancements, we aim to provide a comprehensive understanding of the practical applications of ABs in the context of disease diagnosis and treatment.

Application of ABs in the prevention and diagnosis of diseases

ABs have emerged as promising clinical diagnostic biomarkers with significant implications for various aspects of human health and disease. This chapter provides a comprehensive review of the applications of ABs as biomarkers in disease prevention and diagnosis. Specifically, we delve into their role in diabetes prevention, inflammation, cancer, and cardiovascular disease [135–139].

ABs as drug candidates to prevent type 1 diabetes

Type I diabetes is an characterized by autoimmune response resulting in decreased insulin secretion and elevated blood glucose [135]. In recent studies, ABs generated by islet β cells have shown potential in preventing the development of type 1 diabetes by modulating the immune response [125]. The ABs released by dying islet β cells play a crucial role in preventing the cytotoxicity of these cells and stimulating the body’s immune response as antigens to inhibit the autoimmune response [125]. Studies involving the injection of dendritic cells containing such ABs into mice have yielded promising results. These studies showed a significant reduction in the incidence of type I diabetes among the treated mice [125].

ABs as a potential diagnostic biomarker for graft rejection

In the pathology of intestinal transplants (ITx), crypt apoptosis in the intestinal epithelium plays a crucial role in diagnosing graft-versus-host disease (GVHD) and acute cellular rejection (ACR) [140]. The number of ABs observed in the crypts is used as a diagnostic feature [41, 141–143]. In normal cases of ITx, 2 or fewer ABs in 10 consecutive crypts are considered within the normal range. If there are 6 ABs, it is indicative of mild ACR. However, when 3 to 5 ABs are present, the diagnosis becomes problematic and is often classified as indeterminate for ACR [144]. For GVHD, the minimum diagnostic threshold is controversial and depends on the apoptotic body count (ABC) observed [145]. The specific number of ABs required for a diagnosis of GVHD may vary. The assessment of crypt apoptosis and ABC is an essential component in the diagnosis of GVHD and ACR in ITx. It is important for pathologists to carefully evaluate and consider the presence and quantity of ABs to make accurate diagnostic interpretations. Furthermore, some studies have found that ABs derived from T lymphocytes are phagocytosed in histological biopsies of patients who have undergone intestinal transplantation [146]. This phenomenon can serve as a basis for early diagnosis of ACR, providing patients with timely diagnosis and treatment opportunities while minimizing intestinal mucosal damage [146].In recent studies, it was found that the number of ABs in patients with oral squamous cell carcinoma (OSCC) without regional lymph node metastasis was significantly higher than that in patients with regional lymph node metastasis, suggesting that the number of ABs may be used as a good parameter to show the possibility of regional lymph node involvement in OSCC patients without lymph node involvement [147]. These findings emphasize the potential utility of ABs as valuable diagnostic biomarkers for assessing cellular rejection and related diseases. By analyzing ABs in biopsy samples, clinicians can gain insights into the underlying pathological processes and make informed decisions regarding patient management and treatment strategies.

ABs as a potential diagnostic biomarker for autoimmune hepatitis (AIH) and embryonal rhabdomyosarcoma (ERMS)

ABs show promise in the diagnosis of AIH. In a study, it was found that the count of ABs in the portal area is associated with the pattern and timing of AIH onset, and it can be used as a diagnostic criterion for AIH [148]. The research revealed that patients undergoing their first liver biopsy had a higher count of ABs compared to follow-up patients, and this count was closely correlated with inflammation. Additionally, incorporating the count of ABs in the portal area as a variable in the AIH scoring system increased the number of patients classified as "definite" AIH [148]. In addition, ABs serve as important indicators for the diagnosis of ERMS [149]. A study conducted on adult females analyzed 25 cases of ERMS and observed that tumor samples exhibited areas of high cell density, often accompanied by ABs and mitotic figures. This suggests a potential role for ABs in the development of ERMS [149]. The study also found co-expression of desmin and myogenin, as demonstrated by immunohistochemical staining, in the tumor samples. The co-expression of these two proteins is a typical feature of ERMS. Additionally, there was a significant increase in proliferative activity, indicated by Ki-67 expression, within the tumor samples. These findings further support the potential association between ABs and the development and progression of ERMS. Therefore, the presence of ABs, their co-expression with desmin and myogenin, and increased proliferative activity can serve as important indicators in the diagnosis of ERMS [149].

Biomolecules carried by ABs are potential biomarkers for disease diagnosis

ABs, as mentioned earlier, have been identified as potential candidates for disease diagnosis based on clinical investigations and histopathological examinations. However, there still exist some limitations such as low sensitivity and difficulty in detecting ABs in hidden areas. ABs extracted from body fluids such as blood, urine, and intestinal tract also have the potential to be used as disease diagnostics. Many studies have shown that compared with the ABs extracted from healthy individuals, the contents of ABs extracted from patients with diseases are different [139]. Therefore, ABs have the potential to develop into clinical samples for disease diagnosis. In addition, for patients, detecting ABs is not only less invasive and risky but also more sensitive to monitoring disease progression than current clinical diagnostic methods such as surgery or pathological examination [136]. By leveraging different techniques such as sample selection, preparation, detection, and analysis, ABs derived from various tissues can offer valuable information for the diagnosis of diverse diseases.

Application of ABs in disease treatment

Bone diseases

Recent studies have shown that ABs are mainly used in the treatment of bone defects, bone hyperplasia, osteoarthritis (OA), osteoporosis, and so on (Table 4). Osteoclast-derived ABs have been demonstrated to promote osteogenesis and are being explored for the treatment of bone defects [7, 9, 19, 48]. These ABs could enhance bone formation and regeneration at specific anatomical sites within the bone. Angiogenesis is closely related to osteogenesis, and promoting angiogenesis during bone repair is essential for ideal bone regeneration [150]. Studies have shown that preosteoclast-derived ABs play a crucial role in promoting endothelial cell proliferation, differentiation, migration, and angiogenesis [7, 9]. On the other hand, abnormal metabolism of osteocytes can easily lead to bone hyperplasia [48]. Studies have found that ABs derived from osteocytes can be targeted to specific parts of the bone for bone resorption, which is expected to be used for the treatment of bone hyperplasia [48]. By utilizing the unique targeting capabilities of osteocyte-derived ABs, it may be possible to selectively reduce excessive bone growth in conditions such as bone hyperplasia. In addition, OA is caused by local inflammation of the joint, and macrophage-derived ABs reverse the inflammatory response caused by M1 macrophages by triggering the polarization of macrophages to the M2 phenotype, indicating that the presence of ABs can effectively reduce the inflammatory response in OA patients [151]. Osteoporosis is characterized by an imbalance between osteoblast and osteoclast activity [152, 153]. In recent studies, ABs provide an opportunity to regulate this imbalance and have the potential to be used in the treatment of osteoporosis. For example, ABs derived from BMSCs have shown the ability to rescue damaged BMSCs and promote bone and fat tissue formation [14]. Additionally, miR-30a released by osteoclast-derived ABs has been found to inhibit osteogenesis. Blocking the release of AB miR-30a presents a potential avenue for treating osteoporosis [10]. In summary, the exploration of ABs in the context of bone diseases opens up new possibilities for therapeutic interventions.Table 4 ABs for disease treatment

Classification	Disease	Animal model	Features	Function of ABs	Refs.	
Bone diseases	1. Deossification

2. Hyperosteogeny

3. Osteoporosis

4. OA

	1. Murine bone defect model

2. Calvarial defect mice model

3. Parabiosis mouse model

4. Mouse OA model

	1. Imbalance between osteogenesis and osteoclast

2. Inflammatory reaction

	1. Regulate bone formation/absorption

2. Involve in vascular regeneration and repair

3. Promote bone defect healing

4. Regulate inflammatory factors

	[7, 9, 10, 14, 19, 48, 151]	
Skin wounds	Back skin wound	Skin wound healing model	Incomplete skin, tissue, inflammatory reaction, and vascular injury	Regulate inflammatory factors, involve in vascular regeneration, and accelerate wound healing	[15, 39]	
Tumors	Pancreatic tumors and glioma	Pancreatic tumor microenvironment model and in situ glioma mouse model	Abnormal cell proliferation	Drug delivery, assess drug sensitivity/toxicity, and clear tumor cells	[72, 114, 129, 159, 163]	
Immune-related diseases	1. Cutaneous leishmaniasis

2. Toxoplasma gondii infection

3. Cancers

	1. 4T1 tumor model

2. Murine model of induced immune tolerance

	1. Immune tolerance

2. Immunodeficiency

3. Inflammatory reaction

	1. Activate the immune system

2. Inhibit autoimmunity

3. Regulate inflammatory factors

	[13, 130–132, 165–167, 169, 173]	
CVD	MI, Atherosclerosis, and Dox-induced cardiomyopathy	Mouse models of atherosclerosis and MI	Inflammatory reaction, myocardial damage, angiemphraxis, and angiostenosis	Reduce inflammation, repair damaged myocardium, and improve cardiac systolic function	[8, 23, 38, 69, 70, 133, 171]	
OA osteoarthritis, CVD Cardiovascular diseases, MI Myocardial infarction

Skin wounds

The repair of skin wounds is an extremely complex process, including initiating coagulation function, regulating inflammatory response, and accelerating the formation of granulation tissue [154]. According to the previous study, the morphology, size, and biomarker of ABs can be characterized through scanning electron microscopy analysis, C1q staining, and Annexin V staining (Fig. 8A–C) [39]. ABs can promote angiogenesis and wound repair (Fig. 8D, E, G) by inducing macrophage M2 polarization (Fig. 8F) and enhancing fibroblastmigration [15, 39]. At first, researchers found that mesenchymal stem cells can treat skin wounds by anti-inflammatory, promoting angiogenesis, and inhibiting hypertrophic scar formation [155–158]. In a large number of experimental studies, it has been found that mesenchymal stem cells transplanted into animal skin trauma models undergo extensive apoptosis in a short period [39, 155]. To study the effect of apoptosis on the.Fig. 8 ABs promote wound healing. A Representative image of scanning electron microscopy analysis analysis of MSC-ABs. B Size distribution of MSC-ABs. C Representative images of C1q and Annexin V staining of MSC-ABs. D Representative images of the H&E staining of the skin samples. E Representative images of the Masson staining of the skin samples. F The immunofluorescence images and quantification of the CD206 expression level of macrophages treated with different concentrations of ABs. G Schema of transplanted MSCs undergo apoptosis after transplantation in a mouse skin wound model and releasing ABs, converting macrophages towards the M2 phenotype and further enhancing the functions of fibroblasts, together contributing to the cutaneous wound healing process. Adapted with permission from ref. [39], image licensed under http://creativecommons.org/licenses/by/4.0/

therapeutic effect, the researchers compared the therapeutic effects of mesenchymal stem cells and apoptosis-induced mesenchymal stem cells [155]. The results showed that apoptosis-induced mesenchymal stem cells had better inflammatory regulation ability [155]. It is speculated that a large amount of ABs released during apoptosis may be involved in some of the treatment processes [39]. Compared with direct transplantation of apoptotic mesenchymal stem cells, ABs have a higher retention rate and better safety, which is expected to become a better method for the treatment of skin wounds [39].

Tumors

ABs have a good application prospect in the treatment of tumors. In recent years, ABs have been found to enhance drug penetration and predict drug efficacy in tumor treatment [72, 129, 159]. For the treatment of tumors, existing chemotherapy nanomedicines use the proximity effect to increase their penetration into tumors [72]. Proximity effect refers to the observation in vivo that tumor cells ingesting chemotherapeutic drugs release active drugs after apoptosis [72, 160]. By spreading to previously unaffected surrounding tumor cells, apoptosis occurs while surrounding tumor cells ingest the released drugs [72, 160]. Researchers have found that ABs are the largest proportion of EVs produced after the death of tumor cells caused by chemotherapy drugs, so it is reasonable to suspect that ABs can wrap the remaining unused drugs and be swallowed by adjacent tumor cells [72]. By fluorescence staining of the drug, the fluorescence of ABs produced by the drug after acting on tumor cells was observed, indicating that the remaining drug was stored in the ABs released by apoptotic cells [72]. This finding highlights the importance of ABs participating in the proximity effect in the process of drug treatment of tumors and provides new insights into the deep penetration of tumors. On the other hand, many researchers hope to achieve more accurate removal of tumor cells while retaining the ability to deliver drugs by modifying ABs. Studies have shown that tumor-associated macrophages are important participants in the tumor microenvironment [159]. However, there are few anti-tumor drugs targeting these cells in clinical practice [159]. MMP2 is a recognized tumor diagnostic marker [161]. The researchers determined that MMP2-sensitive AB mimic nanoparticles can selectively target tumor-associated macrophages by fluorescence staining experiments [159]. Therefore, it is expected to achieve tumor treatment by loading related anti-tumor drugs on these simulated ABs. In addition, due to the BBB limiting the entry of chemotherapeutic drugs into the brain, non-brain-targeted nanomedicines for brain cancer are not effective [162]. Based on this situation, researchers prepared ABs loaded with doxorubicin and indocyanine green and found that they could actively cross the BBB of glioma mice and release drugs, which significantly prolonged the life span of glioma mice [163].

After cancer patients are treated with chemotherapeutic drugs, the ability to quickly and sensitively predict drug response and toxicity using an in vitro model of patient-derived tumors is crucial for evaluating the efficacy of chemotherapy. At present, the commonly used clinical method is to image the adherent cells after culturing the tumor cells during the treatment process or to detect the fluorescence staining of apoptotic markers by FCM after extracting the tumor cells [129]. The above methods need cell culture and extraction of tumor cells. Researchers have found that drug-treated tumor cells can release ABs in the culture medium, which can be used as potential markers of drug sensitivity without the need to extract cells during culture [129]. However, this method requires the application of high-throughput single-particle impedance FCM to better quantify ABs with compositional diversity [129]. The above research is expected to simplify the process of tumor treatment effect evaluation by further developing related detection techniques and promoting the update and development of clinical detection techniques.

However, ABs may also promote the growth of tumor cells. Studies have found that tumor cell-derived ABs can induce the up-regulation of programmed death ligand 1 in macrophages in the tumor microenvironment [114]. When macrophages express programmed death ligand 1, they can directly bind to programmed death ligand 1 expressed on the surface of tumor cells, thereby inhibiting macrophage phagocytosis of tumor cells [164]. Therefore, further studies are needed to determine the specific role of ABs in the tumor microenvironment if treatment is to be achieved by inhibiting the growth of tumor cells.

Immune disorders

ABs have shown good application prospects in the treatment of immune system-related diseases. Studies have shown that the clearance of ABs in the immune response plays an important role in the maintenance of immune tolerance [165, 166]. For example, patients with systemic lupus erythematosus have the problem of impaired clearance of ABs, which in turn leads to the accumulation of cellular substances containing autoantigens and triggers an autoimmune response [165, 166]. Therefore, researchers are committed to the treatment of autoimmune diseases by studying related substances that can promote the phagocytosis of ABs. Studies have shown that leptin can effectively enhance the phagocytosis of ABs by macrophages in lupus mice [165].

In recent years, researchers hope to use ABs to produce vaccines with more excellent characteristics such as simple manufacture and low toxicity, to achieve the treatment and prevention of related diseases. ABs are selected based on the following characteristics: (1) ABs contain PS and phosphatidylcholine on the surface, which is conducive to the recognition and removal of ABs by antigen-presenting cells such as macrophages [130, 131, 167–169] and (2) ABs contain complex components from dead cells. As a vaccine, ABs can also be used as an immune adjuvant to stimulate specific cellular immune responses and enhance the body's immune response [13, 130, 131, 167, 169]. Researchers induced apoptosis of macrophages infected with Leishmania and Hela cells infected with Toxoplasma gondii, and extracted ABs released by apoptotic cells [130, 167]. Subsequent experiments such as lymphocyte proliferation proved that these ABs can stimulate the body to produce an immune response and have a protective effect when attacked by parasites [130, 167].

Clinical trials have shown that dendritic cells that internalize chronic lymphocytic leukemia cell ABs can be used as a vaccine to stimulate the body to produce anti-leukemia T-cell responses [131]. However, due to the limited number of participants in the trial, it is difficult to accurately predict the efficacy [131]. The lack of clinical data highlights the need to develop more effective vaccine strategies in malignant tumors, and it is expected to establish more accurate criteria for evaluating the immune response induced by leukemia vaccines by increasing the number of trials.

CVD

ABs have good application prospects in the treatment of various CVDs, including atherosclerosis, MI, cardiomyopathy, and so on. Atherosclerosis is a long-term chronic disease in which lipids and immune cells are deposited in the arteries, and the plaques formed by deposition are prone to inflammation and damage the vascular structure to affect the blood supply of patients [170]. If no reasonable intervention and treatment measures are taken, coronary artery blockage may occur and lead to MI [170]. Therefore, controlling plaque inflammation is essential for the treatment of atherosclerosis and MI. However, the existing oral or intravenous anti-inflammatory drugs make it difficult to achieve the desired anti-inflammatory effect because they cannot accurately accumulate at the plaque [133]. It can be seen from the previous article that macrophages can recognize and engulf ABs, and ABs can trigger macrophages to polarize to the M2 phenotype to promote anti-inflammatory effects [15, 39]. Therefore, researchers have encapsulated anti-inflammatory drugs into ABs (Fig. 9A) and found that modified ABs can increase the number of anti-inflammatory macrophages (Fig. 9B), which could be efficient for MI and atherosclerosis treatment (Fig. 9C) [38, 133]. This indicates that the presence of ABs can enable anti-inflammatory drugs to accurately target plaques and enhance the body's anti-inflammatory response, highlighting the potential of ABs as a therapeutic measure for atherosclerosis. On the other hand, repairing vascular injury is also one of the important therapeutic approaches. Studies have shown that ABs derived from ECs promote the repair of vascular endothelium and reduce atherosclerotic plaques [8, 23, 171].Fig. 9 Engineering ABs for therapeutic application. A Schematic of engineered neutrophil ABs (eNABs) for MI treatment. B Representative fluorescence images of the macrophage phenotypes and the percentage of the iNOS/CD206-positive population. C Representative echocardiographic images for various groups after 4 weeks. Distance between yellow arrows indicates left ventricular internal end-diastolic dimension (LVIDd) and left ventricular internal end-systolic dimension (LVIDs), respectively. Adapted with permission from ref [38]

Cardiomyopathy is a group of myocardial organic diseases caused by multiple causes. At present, there is no specific treatment for the disease in the clinic [172]. The treatment principle is to improve the clinical symptoms and improve the long-term survival rate [172]. However, studies have shown that stem cells can repair damaged myocardium, a method that may achieve a cure for cardiomyopathy [69, 70, 171]. Researchers have found that ABs of cardiomyocytes and fibroblasts regulate the directional differentiation of CSCs [69, 70, 171]. Among them, cardiomyocyte-derived ABs increase myocardial contractility, while fibroblast-derived ABs decrease myocardial contractility [69, 70, 171]. It is necessary to further study the specific mechanism of ABs acting on the myocardium in order to develop targeted drugs that can affect the differentiation direction of stem cells in myocardium and other organs.

Other diseases

The pathogenesis of type 2 diabetes mellitus is diverse. Among them, excessive infiltration of macrophages and pro-inflammatory reactions can cause relatively insufficient insulin secretion resulting in elevated blood glucose, which eventually leads to the occurrence of type 2 diabetes mellitus [174]. Studies have shown that ABs derived from BMSCs induce the reprogramming of macrophages at the transcriptional level, thereby inhibiting the aggregation of macrophages in the liver and promoting the transformation of macrophages into anti-inflammatory phenotypes [40]. The endoplasmic reticulum (ER) calcium-binding protein (CRT) is exposed to the surface of ABs, which mediates the uptake of ABs by macrophages, and reduces macrophage infiltration and pro-inflammatory response, thereby improving the body's glucose tolerance, reducing insulin resistance, and improving liver steatosis [40]. These findings highlight the ability of ABs to regulate the homeostasis of liver macrophages, but the response of CRT to other cells is still uncertain. Therefore, it is necessary to further study the signal molecules and pathways involved in the treatment of type II diabetes by ABs.

Intrauterine adhesions are caused by uterine trauma leading to endometrial fibrosis and partial or total occlusion of the uterine cavity [175]. Studies have shown that ABs derived from mesenchymal stem cells reduce endometrial fibrosis and induce endometrial regeneration by inducing macrophages to transform into anti-inflammatory phenotypes, promoting cell proliferation and angiogenesis [134]. The results showed that the injection of ABs-loaded hyaluronic acid hydrogel could effectively repair the endometrium and restore the fertility of the body [134]. The above studies have shown the good potential of ABs as therapeutic vesicles, which is expected to develop a clinically feasible alternative method for the treatment of intrauterine adhesions.

Tailoring of ABs

ABs, as special EVs, not only have potential in disease diagnosis but also show excellent therapeutic potential by delivering various biomolecules for intercellular communication. ABs have been designed in various ways for disease treatment, especially in drug delivery. In recent years, a series of drug-loading strategies based on ABs have been developed to deliver active drug components to various target organs, tissues, or cells [74, 176]. In order to further enhance the therapeutic effect of ABs, a series of engineering modification methods have been developed such as surface modification of ABs and biomimetic ABs [177]. The recent progress emphasizes the potential of engineered ABs for drug delivery. In this section, we describe the summarized drug-loading strategies of ABs as well as engineering modification methods and biomimetic strategies.

Construction of engineered drug-loaded ABs

At present, drug loading of ABs can be achieved by transfection, co-incubation, and membrane coating (Fig. 10). Transfection refers to the introduction of exogenous RNA or DNA fragments into cells under certain specific conditions to obtain new phenotypes and functions [178]. To obtain ABs cell proliferative ABs, miR-221 can be transfected into macrophage-derived ABs using Exo-Fect reagent [67]. Furthermore, to enable drugs to treat diseases through the BBB, a variety of methods have been developed to break this barrier. Among them, the use of ABs membranes to mediate drug brain delivery is very important. The anti-inflammatory drug antisense oligonucleotides were combined with cationic konjac glucomannan (cKGM) to form a CKA complex, which was transfected into cells through the combination of cKGM and the mannose receptor on the cell surface. Ultraviolet irradiation-induced ABs exert anti-inflammatory effects. CD44v6 on the surface of ABs facilitates the penetration of the blood–brain barrier and achieves drug delivery in the brain [176]. In addition, to obtain ABs that can enhance the immune response, influenza virus hemagglutinin (HA) and nucleoprotein (NP) were introduced into cells through transient transfection, and these ABs can be engulfed by antigen-presenting cells (APC) to enhance the immune response of T and B cells, providing new ideas for immunotherapy [179].Fig. 10 Drug loading strategies for ABs. A transfection, B co-incubation, and C membrane coating. Created with BioRender.com

In addition to cell transfection, co-incubation is a commonly employed method for loading drugs. During co-incubation, drugs are exposed to cells, and in some cases, certain drugs can directly induce apoptosis, resulting in the formation of drug-loaded ABs. For example, research has shown that loading cisplatin and the hypoxia-activated prodrug PR104A into nanoparticles and co-cultivating with 4T1 cells can directly kill externally nonmonic tumor cells with cisplatin and form ABs, while PR104A enters the hypoxic tumor cells within ABs to further exert its cytotoxic effects, achieving deep penetration in tumors [180]. However, for some drugs, artificial induction of apoptosis is required within the cells to obtain ABs loaded with the drugs. For instance, another approach is to co-cultivate cytosine-phosphoric acid-guanine (CpG) adjuvant with 4T1 cells and induce apoptosis with streptolysin, resulting in ABs carrying CpG as cancer vaccines. This vaccine can target macrophages and promote their polarization into M1 type, improving the immune-suppressive microenvironment and enhancing cancer treatment efficacy [132]. Moreover, CpG can also be modified onto gold and silver nanorods, which are then co-incubated with tumor cells to generate ABs loaded with nanodrugs. Based on the photothermal effect of nanorods and the immune activation ability of CpG, these ABs can not only effectively eliminate primary tumors but also prevent tumor metastasis and recurrence [181]. In addition to CpG, Cyclic 2′,3′-GMP-AMP (cGAMP), known as a stimulator of interferon genes (STING) pathway agonist, has emerged as a promising immunotherapy drug capable of enhancing innate immunity [182–184]. When cGAMP is co-incubated with tumor cells, the generated ABs are easily engulfed by APCs, thereby augmenting the body's immune response [185].

The membrane of ABs contains various 'eat me' signaling molecules, such as PS, ICAM-3, C1q, and others, which enable specific uptake of ABs by cells [159, 186]. Utilizing ABs in drug delivery processes can enhance delivery efficiency. However, the large content of ABs significantly reduces the drug load, necessitating further investigation into its safety. Therefore, separating the ABs membrane for drug encapsulation not only improves the loading efficiency but also increases the drug stability. Dou et al. isolated ABs membrane from T cells by ultrasonic treatment to form apoptotic ghosts, which were pre-loaded with Mesoporous Silica Nanoparticles (MSNs) containing anti-inflammatory agents miR-21 and curcumin [187, 188]. Purified AB ghosts were wrapped on the surface of MSN, forming chimeric ABs (cABs) [128]. Due to the inflammatory targeting and drug release properties of AB ghosts, cABs can target macrophages in inflammatory regions and promote their polarization into M2 type, regulating inflammatory response [128]. Another method involves obtaining neutrophil-derived ABs membrane (NABM) through ultrasonic treatment and mixing with MSNs carrying the anti-inflammatory drug hexyl 5-aminolevulinate hydrochloride (HAL), followed by co-extruded to engineered neutrophil ABs (eNABs) that actively target macrophages [38]. After drug release, eNABs produce anti-inflammatory bilirubin, further enhancing the anti-inflammatory effect [38]. Furthermore, copper-modified nanoparticles with antioxidant properties can be encapsulated in NABM to improve local inflammatory response [189].

Surface functionalization of ABs

As a type of EVs, ABs possess an outer membrane that comes from the cell membrane, exhibiting the structure of a phospholipid bilayer, protein, and cholesterol. According to the characteristics of membrane structure, numerous modification methods have been developed in recent years to enhance the functionalities of these EVs, including therapeutic capabilities, targeted delivery, evasion of clearance mechanisms, and more [190–194]. Specifically, several strategies have been employed, including pre-isolation modification and post-isolation modification (Fig. 11).Fig. 11 Potential feasible methods for surface modification of ABs. Created with BioRender.com

Pre-isolation modification

Pre-isolation modification includes genetic, metabolic, and direct parent cell membrane engineering approaches. Among them, genetic engineering refers to the enrichment of target proteins in EVs by transfecting specific gene fragments into parental cells. Surface-modified EVs by genetic engineering are endowed with targeting and specific [195–198], and can also be used in engineered EVs to allow fluorescent, luminescent, or radioactive tracking [199, 200]. Metabolic engineering produces EVs with modified proteins, lipids, or glycans on the surface by adding synthetic modified amino acids, lipids, glycans, or oligonucleotides to the culture medium of parental cells. Through the endogenous synthesis and modification process of cells, the need for gene manipulation is avoided and the functionalization of EVs is achieved [201–204]. Direct parent cell membrane engineering directly transforms the parental cell membrane. By fusing functional liposomes with the parental cell membrane, EVs containing a special membrane surface are obtained. This approach applies to engineering EVs with various functional moieties[205].

Post-isolation-modification

Post-isolation modification can be roughly divided into methods based on physical interactions and methods based on chemical modifications on the vesicles’ surface. At present, the common physical surface engineering methods of EVs include electroporation, freeze–thaw, extrusion, and co-incubation. These methods can temporarily destroy the lipid structure of the membrane and allow the EV membrane to penetrate for cargo loading and surface functionalization. Electroporation is a technology that uses an electric field to temporarily destroy the membrane structure, which allows exogenous substances to enter the membrane of EVs, thereby improving the targeting ability of EVs [206–208]. In addition to electroporation, freeze–thaw is also an important method for surface penetration and modification of EVs. Using freeze–thaw technology, the peptide and EVs are shaken together in an ice bath to integrate the target peptide onto the surface of EVs [209–211]. Extrusion is a common physical modification technique that encapsulates EV films onto different nanoparticles, which are protected from phagocytosis by cells by encapsulating nanoparticles [212–215]. Co-incubation is a common method to introduce targeted peptides into the surface of EVs. This process involves incubating EVs with a targeted peptide, and EVs containing the targeted peptide on the surface can bind to specific receptors on the target cells [216].

Chemical modification

Chemical modification includes covalent modification and non-covalent modification. The widely used strategies for covalent conjugation include the biorthogonal click chemistry, the thiol–maleimide coupling, and EDC–NHS coupling [217–219]. Click chemistry azide–alkyne cycloaddition is a reaction between an alkyne and an azide, involving the catalysis of a triazole linkage by copper. The thiol–maleimide coupling reaction involves adding maleimide to the sulfhydryl groups on the surface of EVs. EDC–NHS coupling could be used for conjugating peptides, proteins, antibodies, and so on to the AB surface. Unlike covalent modifications, non-covalent modifications correspond to AB conjugation via weak interactions, including electrostatic, hydrophobic, or ligand-receptor interactions by nature [203, 220–222]. The surface modification of ABs by electrostatic interaction is achieved by adding functional fragments, which can make ABs positively charged and target negatively charged target cells, and enhance the targeting of ABs to biofilms. The hydrophobic interaction between the vesicles and the liposomes, the liposome membrane was functionalized with peptides, antibodies, or polyethylene glycol (PEG), and then the outer vesicles and the liposome membrane was fused by freeze–thaw method to improve the targeting of the outer vesicles. Ligand-receptor interactions take advantage of the natural receptors present over the extracellular surface vesicles to attach ligands to improve ABs’ target specificity by ligand coupling [216, 223, 224]. In a word, the surface modification methods for ABs include pre-isolation-modification i.e., genetic, metabolic, and direct parent cell membrane engineering methods, and post-isolation-modification i.e., physical interactions and chemical modifications [225–228]. Although these methods can improve the function of EVs, there are still many problems to be solved before these functionalized external vesicles, including ABs, can be applied to the clinic, such as safety issues and clinical evaluation [229–231].

Biomimetic ABs

Natural ABs are limited in terms of stability and yield, making it challenging to utilize them for large-scale clinical therapy. To address this issue, a series of synthetic "biomimetic ABs" strategies have been developed. These strategies involve simulating the “eat me” signal of ABs to prepare nanomaterials or liposomes that contain PS (Fig. 12) [232]. Nanomaterials are extensively employed in biomedical research due to their distinctive physical and chemical properties. Drawing upon the ease of recognition and engulfment exhibited by ABs, researchers have devised a strategy to develop ABs-triggered nanoparticles. According to this strategy, PLGA nanoparticles were first synthesized, and then ABs-inspired nanoparticles were obtained by co-extrusion by coating cell membrane containing PS on PLGA nanoparticles [232–240]. These AB-inspired PS/membrane-coated nanoparticles (PS-MNPs) are better engulfed by macrophages and have anti-inflammatory properties. To enhance the performance of the nanomaterial, researchers further modified it by incorporating acid-sensitive PEG. This modification enables the nanomaterial to not only exhibit the phagocytic properties of ABs and anti-inflammatory effects but also respond to inflammation through pH changes [233]. In addition to modifying PS on the surface, researchers have constructed an apoptotic cell-inspired deformable PS-containing nanoliposome. Compared with the nanomaterials simply modified with PS, the elasticity and surface properties of the coupled nanomaterials can better regulate the macrophage-mediated inflammatory response, and bind to macrophages for a longer time and better effect [235, 236]. The softness of nanomaterials may enhance the therapeutic effect of macrophage-mediated nanosystems, which will provide new ideas for the design of engineered nanotherapeutic drugs.Fig. 12 Engineering modification of ABs. Created with BioRender.com

In addition to the extrusion methods, AB-inspired materials can also be obtained by the filming-rehydration method. In this method, the lipid film was first prepared, and then a suitable aqueous medium was added. After that, the liposome was mixed with PS, homogenized by an ultrasonic probe, and obtained by a microporous membrane filter [133, 241–243]. In the preparation process of PS liposomes, drugs such as metformin and alendronate can also be added, and the drugs can be transported to the target position by the targeting effect of PS [236, 241, 242].

In addition to filming-rehydration and co-extrusion, biomimetic ABs can also be achieved by using apoptotic cell membrane-inspired phosphoserine polymers. In 2017, researchers demonstrated for the first time that phosphoserine polymers inspired by apoptotic cell membranes can protect mouse macrophages from lipopolysaccharide-induced inflammation and inhibit macrophage activation. In this study, the researchers synthesized water-soluble methacryloyloxyethyl phosphorylserine (MPS) using the phosphoramidite method. Firstly, they used 2-hydroxyethyl methacrylate and tert-butyl tetraisopropyl phosphate diamine as raw materials to synthesize MPS by the phosphoric acid diamine method. Secondly, they synthesized MPS and phosphorylcholine at a copolymerization ratio of 1: 9, which mimics apoptotic cell membranes [244]. In summary, the biomimetic ABs strategy has led to the development of various biomimetic materials through extrusion, filming-rehydration, phosphoramidite method, and other methods. It is anticipated that more nanomaterials will be developed in the future utilizing ABs for the treatment of various diseases.

Challenges and prospects

As cell-derived natural vesicles, ABs have biological advantages over other nanomaterials [245]. In addition, they carry effective biological molecules, which makes them ideal candidates for disease diagnosis and treatment [128–136]. In recent years, a series of engineered modification strategies have been developed to expand the therapeutic targeting and efficacy of ABs, to maximize the therapeutic effects [190–194]. The strategies include drug-loading ABs, surface modification strategies, and biomimetic ABs. Owing to numerous modification methods, ABs have been utilized in various medical fields, including but not limited to drug delivery, tissue regeneration, immunotherapy, vaccine development, and disease therapy. Although engineered ABs possess advantages compared with natural ABs, the clinical translation of engineered ABs faces many challenges. First, although multiple methods for ABs isolation and characterization exist, there is still a lack of standardization in efficient separation and identification strategies, which hinders the large-scale production of ABs for clinical use. Furthermore, the loading efficiency of therapeutically effective medications remains insufficient, which makes its improvement a primary focus of future research. Lastly, the surface modification of ABs could lead to the disruption of ABs membrane structure, thus affecting the structure stability, cellular uptake pathways, and regulatory function of ABs. In conclusion, despite some potential setbacks and challenges, engineering-modified ABs hold promise for robust use in clinical settings, and further studies are needed to assess the safety and efficacy of the new generation of engineered ABs.

Conclusion

In summary, the biological characteristics and physiological functions of ABs make them promising therapeutic agents. It has been found that engineering manipulation of ABs can enhance their functions, including therapeutic potential, targeted delivery, evasion of clearance mechanisms, and more, thus accelerating the progress of the clinical application of ABs. However, given the shortcomings of the current modification methods of ABs, more strategies are needed to solve the safety and functional integrity issues, which may make the clinical application of ABs more feasible and provide new prospects for the diagnosis and treatment of various diseases.

Abbreviations

ABC Apoptotic body count

ABs Apoptotic bodies

ACR Acute cellular rejection

AIH Autoimmune hepatitis

AKT Protein kinase B

Ambra1 Activating molecule in beclin1-regulated autophagy

AMN Apoptotic microtubule network

APC Abdominal antigen-presenting cells

Ara-C Cytosine arabinoside

ATF6 Activating transcription factor 6

BAI1 Brain-specific angiogenesis inhibitor 1

BBB Blood–brain barrier

BMM Bone marrow macrophage

BMSCs Bone marrow mesenchymal stem cells

cABs Chimeric ABs

Caspase-3 Cysteine protease 3

CDKN1B Cyclin-dependent kinase inhibitor 1B

cGAMP Cyclic 2',3'-GMP-AMP

cKGM Cationic konjac glucomannan

COX2 Cyclooxygenase-2

CpG Cytosine-phosphoric acid-guanine

CRT Calreticulin

Cryo-TEM Low-temperature transmission electron microscopy

CSCs Cardiac stem cells

CSF Cerebrospinal fluid

CVD Cardiovascular diseases

CYTC Cytochrome C

ECs Endothelial cells

eNABs Engineered neutrophil ABs

EP Prostaglandin receptor

EPCs Endothelial progenitor cells

ER Endoplasmic reticulum

ERMS Embryonal rhabdomyosarcoma

EVs Extracellular vesicles

FACS Fluorescence-activated cell sorting

FCM Flow cytometry

GlcNAc N-acetylglucosamine

GLPMs GATA6 large peritoneal macrophages

GVHD Graft-versus-host disease

HA Hemagglutinin

HAL Hydrochloride

HGF Horizontal gene transfer

HIF-1α Hypoxia-inducible factor-1α

HUVACs Human umbilical vein endothelial cells

ICAM Intercellular adhesion molecules

ICG Indocyanine green

IFN Interferon

IGF2BP 3 Insulin growth factor 2 mRNA-binding protein 3

IL Interleukin

iPGE2 Intracellular prostaglandin E2

IRE1 Inositol-requiring transmembrane kinase endoribonuclease-1

ITx Intestinal transplants

LFA-1 Lymphocyte function-associated antigen 1

LIMK1 Lim domain kinase 1

lncRNAs Long non-coding RNAs

LPS Lipopolysaccharide

MAPK Mitogen-activated protein kinase

MerTK Tyrosine-protein kinase Mer

MI Myocardial infarction

miRNAs MicroRNAs

MLCK Myosin light chain kinase

mOC Mature osteoclast cell

MPS Methacryloyloxyethyl phosphorylserine

MSC Marrow mesenchymal stem cells

MSNs Mesoporous Silica Nanoparticles

mTOR Mammalian target of rapamycin

NABM Neutrophil-derived ABs membrane

NO Nitric oxide

NP: Nucleoprotein

NTA Nanoparticle tracking technology

OA Osteoarthritis

OSCC Oral squamous cell carcinoma

PAK2 P21-activated kinase

PANX1 Pan-catenin 1

PDGF-BB Platelet-derived growth factor-BB

PD-L1 Programmed cell death ligand 1

PERK Protein kinase RNA–like endoplasmic reticulum kinase

PI3K Phosphoinositide 3-kinase

PlexB2 Plexus B2

pOC Pre-osteoclast cell

poly (MPC) Synthesized MPS and phosphorylcholine

PS Phosphatidylserine

PS-MNPs PS/membrane-coated nanoparticles

PTPRC Protein tyrosine phosphatase receptor C

RANK Receptor activator of nuclear factor kappa B

RANKL Receptor activator of nuclear factor kappa B ligand

RCCS Rotating cell culture system

RGS Regulator of G protein signaling

ROCK1 Rho-associated protein kinase 1

S6K S6 kinase

SMAD2 Drosophila mothers against decapentaplegic protein 2

STING Stimulator of interferon genes

TEM Transmission electron microscopy

TFEB Transcription factor EB

TGF-β Transforming growth factor-β

Th1 T helper 1

TIM T cell immunoglobulin mucin proteins

TNF Tumor necrosis factor

TSP Thrombospondin

VEGF Vascular endothelial growth factor

Acknowledgements

Not applicable.

Author contributions

X.M., X.W., W.Y., and K.H. contributed to the conception, design, writing, and drawing of the images. C.C. edited the manuscript and drew images. J.P. and Q.Z designed the conception, reviewed the manuscript, and funded this work.

Funding

This research was funded by the National Natural Science Foundation of China (32301129, 31801152), the Science and Technology Planning Projects of Guangzhou City, China (No. 202201020203, 202201020117), Guangzhou Science and Technology Plan Project, China (2023B03J1240), the Special projects in key fields of Guangdong Colleges and Universities, China (No.2021ZDZX2058), and the Undergraduate Teaching Quality and Teaching Reform Engineering Projects of Guangzhou Medical University (No. 2021-28-2, 2021-159-48, 2022-124-1).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Kerr JFR Wyllie AH Currie AR Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics Br J Cancer 1972 26 4 239 257 10.1038/bjc.1972.33 4561027
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.4561027 10.1038/bjc.1972.33
2. Li X Liu Y Liu X Du J Bhawal UK Xu J Guo L Liu Y Advances in the therapeutic effects of apoptotic bodies on systemic diseases Int J Mol Sci 2022 23 15 8202 10.3390/ijms23158202 35897778
Li X, Liu Y, Liu X, Du J, Bhawal UK, Xu J, Guo L, Liu Y. Advances in the therapeutic effects of apoptotic bodies on systemic diseases. Int J Mol Sci. 2022;23(15):8202.35897778 10.3390/ijms23158202
3. Santagostino SF Assenmacher CA Tarrant JC Adedeji AO Radaelli E Mechanisms of regulated cell death: current perspectives Vet Pathol 2021 58 4 596 623 10.1177/03009858211005537 34039100
Santagostino SF, Assenmacher CA, Tarrant JC, Adedeji AO, Radaelli E. Mechanisms of regulated cell death: current perspectives. Vet Pathol. 2021;58(4):596–623.34039100 10.1177/03009858211005537
4. Kerr JFR History of the events leading to the formulation of the apoptosis concept Toxicology 2002 181–182 471 474 10.1016/S0300-483X(02)00457-2 12505355
Kerr JFR. History of the events leading to the formulation of the apoptosis concept. Toxicology. 2002;181–182:471–4.12505355 10.1016/S0300-483X(02)00457-2
5. Searle J Kerr JF Bishop CJ Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance Pathol Annu 1982 17 Pt 2 229 259 7182752
Searle J, Kerr JF, Bishop CJ. Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathol Annu. 1982;17(Pt 2):229–59.7182752
6. Xu X Lai Y Hua ZC Apoptosis and apoptotic body: disease message and therapeutic target potentials Biosci Rep 2019 10.1042/BSR20180992 31820803
X. Xu, Y. Lai, Z.C. Hua, Apoptosis and apoptotic body: disease message and therapeutic target potentials, Biosci Rep (2019) . 10.1042/BSR20180992.31820803 10.1042/BSR20180992
7. Ma Q Liang M Wu Y Luo F Ma Z Dong S Xu J Dou C Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling Bone Res 2021 9 1 5 10.1038/s41413-020-00121-1 33431863
Ma Q, Liang M, Wu Y, Luo F, Ma Z, Dong S, Xu J, Dou C. Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling. Bone Res. 2021;9(1):5.33431863 10.1038/s41413-020-00121-1
8. Liu H Liu S Qiu X Yang X Bao L Pu F Liu X Li C Xuan K Zhou J Deng Z Liu S Jin Y Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells Autophagy 2020 16 12 2140 2155 10.1080/15548627.2020.1717128 31959090
Liu H, Liu S, Qiu X, Yang X, Bao L, Pu F, Liu X, Li C, Xuan K, Zhou J, Deng Z, Liu S, Jin Y. Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells. Autophagy. 2020;16(12):2140–55.31959090 10.1080/15548627.2020.1717128
9. Ma QY Liang MM Limjunyawong N Dan Y Xing JC Li JM Xu JZ Dou C Osteoclast-derived apoptotic bodies show extended biological effects of parental cell in promoting bone defect healing Theranostics 2020 10 15 6825 6838 10.7150/thno.45170 32550906
Ma QY, Liang MM, Limjunyawong N, Dan Y, Xing JC, Li JM, Xu JZ, Dou C. Osteoclast-derived apoptotic bodies show extended biological effects of parental cell in promoting bone defect healing. Theranostics. 2020;10(15):6825–38.32550906 10.7150/thno.45170
10. Yiliang F Fenglai Y Effect of osteoclast-derived apoptotic body microR-30a on osteogenic activity Acta Anatomica Sinica 2021 52 4 561 566
Yiliang F, Fenglai Y. Effect of osteoclast-derived apoptotic body microR-30a on osteogenic activity. Acta Anatomica Sinica. 2021;52(4):561–6.
11. Bhatwadekar AD Glenn JV Curtis TM Grant MB Stitt AW Gardiner TA Retinal endothelial cell apoptosis stimulates recruitment of endothelial progenitor cells Invest Ophthalmol Vis Sci 2009 50 10 4967 4973 10.1167/iovs.09-3616 19474402
Bhatwadekar AD, Glenn JV, Curtis TM, Grant MB, Stitt AW, Gardiner TA. Retinal endothelial cell apoptosis stimulates recruitment of endothelial progenitor cells. Invest Ophthalmol Vis Sci. 2009;50(10):4967–73.19474402 10.1167/iovs.09-3616
12. Poon IK Lucas CD Rossi AG Ravichandran KS Apoptotic cell clearance: basic biology and therapeutic potential Nat Rev Immunol 2014 14 3 166 180 10.1038/nri3607 24481336
Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14(3):166–80.24481336 10.1038/nri3607
13. Turiák L Misják P Szabó TG Aradi B Pálóczi K Ozohanics O Drahos L Kittel A Falus A Buzás EI Vékey K Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice J Proteomics 2011 74 10 2025 2033 10.1016/j.jprot.2011.05.023 21635979
Turiák L, Misják P, Szabó TG, Aradi B, Pálóczi K, Ozohanics O, Drahos L, Kittel A, Falus A, Buzás EI, Vékey K. Proteomic characterization of thymocyte-derived microvesicles and apoptotic bodies in BALB/c mice. J Proteomics. 2011;74(10):2025–33.21635979 10.1016/j.jprot.2011.05.023
14. Liu D Kou X Chen C Liu S Liu Y Yu W Yu T Yang R Wang R Zhou Y Shi S Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors Cell Res 2018 28 9 918 933 10.1038/s41422-018-0070-2 30030518
Liu D, Kou X, Chen C, Liu S, Liu Y, Yu W, Yu T, Yang R, Wang R, Zhou Y, Shi S. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res. 2018;28(9):918–33.30030518 10.1038/s41422-018-0070-2
15. Li J Wei C Yang Y Gao Z Guo Z Qi F Apoptotic bodies extracted from adipose mesenchymal stem cells carry microRNA-21-5p to induce M2 polarization of macrophages and augment skin wound healing by targeting KLF6 Burns 2022 48 8 1893 1908 10.1016/j.burns.2021.12.010 35016791
Li J, Wei C, Yang Y, Gao Z, Guo Z, Qi F. Apoptotic bodies extracted from adipose mesenchymal stem cells carry microRNA-21-5p to induce M2 polarization of macrophages and augment skin wound healing by targeting KLF6. Burns. 2022;48(8):1893–908.35016791 10.1016/j.burns.2021.12.010
16. Emamalipour M Seidi K Vahed SZ Jahanban-Esfahlan A Jaymand M Majdi H Amoozgar Z Chitkushev LT Javaheri T Jahanban-Esfahlan R Zare P Horizontal gene transfer: from evolutionary flexibility to disease progression Front Cell Dev Biol 2020 8 229 10.3389/fcell.2020.00229 32509768
Emamalipour M, Seidi K, Vahed SZ, Jahanban-Esfahlan A, Jaymand M, Majdi H, Amoozgar Z, Chitkushev LT, Javaheri T, Jahanban-Esfahlan R, Zare P. Horizontal gene transfer: from evolutionary flexibility to disease progression. Front Cell Dev Biol. 2020;8:229.32509768 10.3389/fcell.2020.00229
17. Garcia-Pastor C Blazquez-Serra R Bosch RJ Lucio Cazana FJ Fernandez-Martinez AB Apoptosis and cell proliferation in proximal tubular cells exposed to apoptotic bodies novel pathophysiological implications in cisplatin-induced renal injury Biochim Biophys Acta Mol Basis Dis 2019 1865 9 2504 2515 10.1016/j.bbadis.2019.06.008 31195118
Garcia-Pastor C, Blazquez-Serra R, Bosch RJ, Lucio Cazana FJ, Fernandez-Martinez AB. Apoptosis and cell proliferation in proximal tubular cells exposed to apoptotic bodies novel pathophysiological implications in cisplatin-induced renal injury. Biochim Biophys Acta Mol Basis Dis. 2019;1865(9):2504–15.31195118 10.1016/j.bbadis.2019.06.008
18. Brock CK Wallin ST Ruiz OE Samms KM Mandal A Sumner EA Eisenhoffer GT Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance Nat Commun 2019 10 1 1044 10.1038/s41467-019-09010-6 30837472
Brock CK, Wallin ST, Ruiz OE, Samms KM, Mandal A, Sumner EA, Eisenhoffer GT. Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance. Nat Commun. 2019;10(1):1044.30837472 10.1038/s41467-019-09010-6
19. Ma Q Liang M Wu Y Ding N Duan L Yu T Bai Y Kang F Dong S Xu J Dou C Mature osteoclast–derived apoptotic bodies promote osteogenic differentiation via RANKL-mediated reverse signaling J Biol Chem 2019 294 29 11240 11247 10.1074/jbc.RA119.007625 31167789
Ma Q, Liang M, Wu Y, Ding N, Duan L, Yu T, Bai Y, Kang F, Dong S, Xu J, Dou C. Mature osteoclast–derived apoptotic bodies promote osteogenic differentiation via RANKL-mediated reverse signaling. J Biol Chem. 2019;294(29):11240–7.31167789 10.1074/jbc.RA119.007625
20. Gou J Li H Bi J Pang X Li X Wang Y Transfer of IGF2BP3 through Ara-C-induced apoptotic bodies promotes survival of recipient cells Front Oncol 2022 12 801226 10.3389/fonc.2022.801226 35615150
Gou J, Li H, Bi J, Pang X, Li X, Wang Y. Transfer of IGF2BP3 through Ara-C-induced apoptotic bodies promotes survival of recipient cells. Front Oncol. 2022;12: 801226.35615150 10.3389/fonc.2022.801226
21. Bernardo-Bermejo S Sánchez-López E Castro-Puyana M Fernández-Martínez AB Lucio-Cazaña FJ Marina ML Exploring the metabolic differences between cisplatin- and uv light-induced apoptotic bodies in HK-2 Cells by an untargeted metabolomics approach Int J Mol Sci 2023 24 8 7237 10.3390/ijms24087237 37108400
Bernardo-Bermejo S, Sánchez-López E, Castro-Puyana M, Fernández-Martínez AB, Lucio-Cazaña FJ, Marina ML. Exploring the metabolic differences between cisplatin- and uv light-induced apoptotic bodies in HK-2 Cells by an untargeted metabolomics approach. Int J Mol Sci. 2023;24(8):7237.37108400 10.3390/ijms24087237
22. Zhou S Li J Zhang X Xiong W MicroRNA-124 modulates neuroinflammation in acute methanol poisoning rats via targeting Krüppel-like factor-6 Bioengineered 2022 13 5 13507 13519 10.1080/21655979.2022.2078549 35658788
Zhou S, Li J, Zhang X, Xiong W. MicroRNA-124 modulates neuroinflammation in acute methanol poisoning rats via targeting Krüppel-like factor-6. Bioengineered. 2022;13(5):13507–19.35658788 10.1080/21655979.2022.2078549
23. Zernecke A Bidzhekov K Noels H Shagdarsuren E Gan L Denecke B Hristov M Koppel T Jahantigh MN Lutgens E Wang S Olson EN Schober A Weber C Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection Sci Signal 2009 10.1126/scisignal.2000610 19996457
Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Koppel T, Jahantigh MN, Lutgens E, Wang S, Olson EN, Schober A, Weber C. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009. 10.1126/scisignal.2000610.19996457 10.1126/scisignal.2000610
24. Hartjes TA Mytnyk S Jenster GW van Steijn V van Royen ME Extracellular vesicle quantification and characterization: common methods and emerging approaches Bioengineering 2019 6 1 7 10.3390/bioengineering6010007 30654439
Hartjes TA, Mytnyk S, Jenster GW, van Steijn V, van Royen ME. Extracellular vesicle quantification and characterization: common methods and emerging approaches. Bioengineering. 2019;6(1):7.30654439 10.3390/bioengineering6010007
25. Liu Y-J Wang C A review of the regulatory mechanisms of extracellular vesicles-mediated intercellular communication Cell Commun Signal 2023 21 1 77 10.1186/s12964-023-01103-6 37055761
Liu Y-J, Wang C. A review of the regulatory mechanisms of extracellular vesicles-mediated intercellular communication. Cell Commun Signal. 2023;21(1):77.37055761 10.1186/s12964-023-01103-6
26. Wu P Zhang B Ocansey DKW Xu W Qian H Extracellular vesicles: a bright star of nanomedicine Biochemistry 2021 269 120467
Wu P, Zhang B, Ocansey DKW, Xu W, Qian H. Extracellular vesicles: a bright star of nanomedicine. Biochemistry. 2021;269: 120467.
27. Caruso S Poon IKH Apoptotic cell-derived extracellular vesicles: more than just debris Front Immunol 2018 9 1486 10.3389/fimmu.2018.01486 30002658
Caruso S, Poon IKH. Apoptotic cell-derived extracellular vesicles: more than just debris. Front Immunol. 2018;9:1486.30002658 10.3389/fimmu.2018.01486
28. Favaloro B Allocati N Graziano V Di Ilio C De Laurenzi V Role of apoptosis in disease Aging 2012 4 5 330 349 10.18632/aging.100459 22683550
Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V. Role of apoptosis in disease. Aging. 2012;4(5):330–49.22683550 10.18632/aging.100459
29. Tixeira R Phan TK Caruso S Shi B Atkin-Smith GK Nedeva C Chow JDY Puthalakath H Hulett MD Herold MJ Poon IKH ROCK1 but not LIMK1 or PAK2 is a key regulator of apoptotic membrane blebbing and cell disassembly Cell Death Differ 2020 27 1 102 116 10.1038/s41418-019-0342-5 31043701
Tixeira R, Phan TK, Caruso S, Shi B, Atkin-Smith GK, Nedeva C, Chow JDY, Puthalakath H, Hulett MD, Herold MJ, Poon IKH. ROCK1 but not LIMK1 or PAK2 is a key regulator of apoptotic membrane blebbing and cell disassembly. Cell Death Differ. 2020;27(1):102–16.31043701 10.1038/s41418-019-0342-5
30. Charras GT Yarrow JC Horton MA Mahadevan L Mitchison TJ Non-equilibration of hydrostatic pressure in blebbing cells Nature 2005 435 7040 365 369 10.1038/nature03550 15902261
Charras GT, Yarrow JC, Horton MA, Mahadevan L, Mitchison TJ. Non-equilibration of hydrostatic pressure in blebbing cells. Nature. 2005;435(7040):365–9.15902261 10.1038/nature03550
31. Khajah MA Luqmani YA Involvement of membrane blebbing in immunological disorders and cancer Med Princ Pract 2016 25 Suppl 2 18 27 10.1159/000441848 26488882
Khajah MA, Luqmani YA. Involvement of membrane blebbing in immunological disorders and cancer. Med Princ Pract. 2016;25(Suppl 2):18–27.26488882 10.1159/000441848
32. Atkin-Smith GK Poon IKH Disassembly of the dying: mechanisms and functions Trends Cell Biol 2017 27 2 151 162 10.1016/j.tcb.2016.08.011 27647018
Atkin-Smith GK, Poon IKH. Disassembly of the dying: mechanisms and functions. Trends Cell Biol. 2017;27(2):151–62.27647018 10.1016/j.tcb.2016.08.011
33. Atkin-Smith GK Tixeira R Paone S Mathivanan S Collins C Liem M Goodall KJ Ravichandran KS Hulett MD Poon IK A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure Nat Commun 2015 6 7439 10.1038/ncomms8439 26074490
Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C, Liem M, Goodall KJ, Ravichandran KS, Hulett MD, Poon IK. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat Commun. 2015;6:7439.26074490 10.1038/ncomms8439
34. Moss DK Betin VM Malesinski SD Lane JD A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation J Cell Sci 2006 119 Pt 11 2362 2374 10.1242/jcs.02959 16723742
Moss DK, Betin VM, Malesinski SD, Lane JD. A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation. J Cell Sci. 2006;119(Pt 11):2362–74.16723742 10.1242/jcs.02959
35. Caruso S Atkin-Smith GK Baxter AA Tixeira R Jiang L Ozkocak DC Santavanond JP Hulett MD Lock P Phan TK Poon IKH Defining the role of cytoskeletal components in the formation of apoptopodia and apoptotic bodies during apoptosis Apoptosis 2019 24 11–12 862 877 10.1007/s10495-019-01565-5 31489517
Caruso S, Atkin-Smith GK, Baxter AA, Tixeira R, Jiang L, Ozkocak DC, Santavanond JP, Hulett MD, Lock P, Phan TK, Poon IKH. Defining the role of cytoskeletal components in the formation of apoptopodia and apoptotic bodies during apoptosis. Apoptosis. 2019;24(11–12):862–77.31489517 10.1007/s10495-019-01565-5
36. Poon IK Chiu YH Armstrong AJ Kinchen JM Juncadella IJ Bayliss DA Ravichandran KS Unexpected link between an antibiotic, pannexin channels and apoptosis Nature 2014 507 7492 329 334 10.1038/nature13147 24646995
Poon IK, Chiu YH, Armstrong AJ, Kinchen JM, Juncadella IJ, Bayliss DA, Ravichandran KS. Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature. 2014;507(7492):329–34.24646995 10.1038/nature13147
37. Jiang L Paone S Caruso S Atkin-Smith GK Phan TK Hulett MD Poon IKH Determining the contents and cell origins of apoptotic bodies by flow cytometry Sci Rep 2017 10.1038/s41598-017-14305-z 29273734
Jiang L, Paone S, Caruso S, Atkin-Smith GK, Phan TK, Hulett MD, Poon IKH. Determining the contents and cell origins of apoptotic bodies by flow cytometry. Sci Rep. 2017. 10.1038/s41598-017-14305-z.29273734 10.1038/s41598-017-14305-z
38. Bao L Dou G Tian R Lv Y Ding F Liu S Zhao R Zhao L Zhou J Weng L Dong Y Li B Liu S Chen X Jin Y Engineered neutrophil apoptotic bodies ameliorate myocardial infarction by promoting macrophage efferocytosis and inflammation resolution Bioact Mater 2022 9 183 197 34820565
Bao L, Dou G, Tian R, Lv Y, Ding F, Liu S, Zhao R, Zhao L, Zhou J, Weng L, Dong Y, Li B, Liu S, Chen X, Jin Y. Engineered neutrophil apoptotic bodies ameliorate myocardial infarction by promoting macrophage efferocytosis and inflammation resolution. Bioact Mater. 2022;9:183–97.34820565
39. Liu J Qiu XY Lv YJ Zheng CX Dong Y Dou G Zhu B Liu AQ Wang W Zhou J Liu SY Liu SY Gao B Jin Y Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages Stem Cell Res Ther 2020 11 1 507 10.1186/s13287-020-02014-w 33246491
Liu J, Qiu XY, Lv YJ, Zheng CX, Dong Y, Dou G, Zhu B, Liu AQ, Wang W, Zhou J, Liu SY, Liu SY, Gao B, Jin Y. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res Ther. 2020;11(1):507.33246491 10.1186/s13287-020-02014-w
40. Zheng C Sui B Zhang X Hu J Chen J Liu J Wu D Ye Q Xiang L Qiu X Liu S Deng Z Zhou J Liu S Shi S Jin Y Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes J Extracell Vesicles 2021 10 7 e12109 10.1002/jev2.12109 34084287
Zheng C, Sui B, Zhang X, Hu J, Chen J, Liu J, Wu D, Ye Q, Xiang L, Qiu X, Liu S, Deng Z, Zhou J, Liu S, Shi S, Jin Y. Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes. J Extracell Vesicles. 2021;10(7): e12109.34084287 10.1002/jev2.12109
41. Hakim SA Abd El-Kareem D Evaluation of crypt apoptotic bodies and apoptotic indices in pediatric celiac disease by routine staining and H2AX immunostaining Int J Immunopathol Pharmacol 2021 35 20587384211026791 10.1177/20587384211026791 34137295
Hakim SA, Abd El-Kareem D. Evaluation of crypt apoptotic bodies and apoptotic indices in pediatric celiac disease by routine staining and H2AX immunostaining. Int J Immunopathol Pharmacol. 2021;35:20587384211026790.34137295 10.1177/20587384211026791
42. Doyle L Wang M Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis Cells 2019 10.3390/cells8070727 31752385
Doyle L, Wang M. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019. 10.3390/cells8070727.31752385 10.3390/cells8070727
43. Cappello F Logozzi M Campanella C Bavisotto CC Marcilla A Properzi F Fais S Exosome levels in human body fluids: a tumor marker by themselves?, European journal of pharmaceutical sciences : official journal of the European federation for Pharmaceut Sci 2017 96 93 98 10.1016/j.ejps.2016.09.010
Cappello F, Logozzi M, Campanella C, Bavisotto CC, Marcilla A, Properzi F, Fais S. Exosome levels in human body fluids: a tumor marker by themselves?, European journal of pharmaceutical sciences : official journal of the European federation for. Pharmaceut Sci. 2017;96:93–8.10.1016/j.ejps.2016.09.010
44. Matsumoto Y Kano M Akutsu Y Hanari N Hoshino I Murakami K Usui A Suito H Takahashi M Otsuka R Xin H Komatsu A Iida K Matsubara H Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma Oncol Rep 2016 36 5 2535 2543 10.3892/or.2016.5066 27599779
Matsumoto Y, Kano M, Akutsu Y, Hanari N, Hoshino I, Murakami K, Usui A, Suito H, Takahashi M, Otsuka R, Xin H, Komatsu A, Iida K, Matsubara H. Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma. Oncol Rep. 2016;36(5):2535–43.27599779 10.3892/or.2016.5066
45. Matsushita H Yang YM Pandol SJ Seki E Exosome migration inhibitory factor as a marker and therapeutic target for pancreatic cancer Gastroenterology 2016 150 4 1033 1035 10.1053/j.gastro.2016.02.051 26922869
Matsushita H, Yang YM, Pandol SJ, Seki E. Exosome migration inhibitory factor as a marker and therapeutic target for pancreatic cancer. Gastroenterology. 2016;150(4):1033–5.26922869 10.1053/j.gastro.2016.02.051
46. Regente M Corti-Monzón G Maldonado AM Pinedo M Jorrín J de la Canal L Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins FEBS Lett 2009 583 20 3363 3366 10.1016/j.febslet.2009.09.041 19796642
Regente M, Corti-Monzón G, Maldonado AM, Pinedo M, Jorrín J, de la Canal L. Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett. 2009;583(20):3363–6.19796642 10.1016/j.febslet.2009.09.041
47. Song J Kim D Han J Kim Y Lee M Jin EJ PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis Clin Exp Med 2015 15 1 121 126 10.1007/s10238-013-0271-4 24722995
Song J, Kim D, Han J, Kim Y, Lee M, Jin EJ. PBMC and exosome-derived Hotair is a critical regulator and potent marker for rheumatoid arthritis. Clin Exp Med. 2015;15(1):121–6.24722995 10.1007/s10238-013-0271-4
48. Kogianni G Mann V Noble BS Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction J Bone Miner Res 2008 23 6 915 927 10.1359/jbmr.080207 18435576
Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localized bone destruction. J Bone Miner Res. 2008;23(6):915–27.18435576 10.1359/jbmr.080207
49. Dieudé M Bell C Turgeon J Beillevaire D Pomerleau L Yang B Hamelin K Qi S Pallet N Béland C Dhahri W Cailhier JF Rousseau M Duchez AC Lévesque T Lau A Rondeau C Gingras D Muruve D Rivard A Cardinal H Perreault C Desjardins M Boilard É Thibault P Hébert MJ The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection Sci Trans Med 2015 10.1126/scitranslmed.aac9816
Dieudé M, Bell C, Turgeon J, Beillevaire D, Pomerleau L, Yang B, Hamelin K, Qi S, Pallet N, Béland C, Dhahri W, Cailhier JF, Rousseau M, Duchez AC, Lévesque T, Lau A, Rondeau C, Gingras D, Muruve D, Rivard A, Cardinal H, Perreault C, Desjardins M, Boilard É, Thibault P, Hébert MJ. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Trans Med. 2015. 10.1126/scitranslmed.aac9816.10.1126/scitranslmed.aac9816
50. O'Brien K Breyne K Ughetto S Laurent LC Breakefield XO RNA delivery by extracellular vesicles in mammalian cells and its applications Nat Rev Mol Cell Biol 2020 21 10 585 606 10.1038/s41580-020-0251-y 32457507
O’Brien K, Breyne K, Ughetto S, Laurent LC, Breakefield XO. RNA delivery by extracellular vesicles in mammalian cells and its applications. Nat Rev Mol Cell Biol. 2020;21(10):585–606.32457507 10.1038/s41580-020-0251-y
51. D'Souza-Schorey C Schorey JS Regulation and mechanisms of extracellular vesicle biogenesis and secretion Essays Biochem 2018 62 2 125 133 10.1042/EBC20170078 29666210
D’Souza-Schorey C, Schorey JS. Regulation and mechanisms of extracellular vesicle biogenesis and secretion. Essays Biochem. 2018;62(2):125–33.29666210 10.1042/EBC20170078
52. van Niel G D'Angelo G Raposo G Shedding light on the cell biology of extracellular vesicles Nat Rev Mol Cell Biol 2018 19 4 213 228 10.1038/nrm.2017.125 29339798
van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28.29339798 10.1038/nrm.2017.125
53. Akers JC Gonda D Kim R Carter BS Chen CC Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies J Neurooncol 2013 113 1 1 11 10.1007/s11060-013-1084-8 23456661
Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113(1):1–11.23456661 10.1007/s11060-013-1084-8
54. Deng F Miller J A review on protein markers of exosome from different bio-resources and the antibodies used for characterization J Histotechnol 2019 42 4 226 239 10.1080/01478885.2019.1646984 31432761
Deng F, Miller J. A review on protein markers of exosome from different bio-resources and the antibodies used for characterization. J Histotechnol. 2019;42(4):226–39.31432761 10.1080/01478885.2019.1646984
55. Franken LE Boekema EJ Stuart, transmission electron microscopy as a tool for the characterization of soft materials: application and interpretation Adv Sci 2017 4 5 1600476 10.1002/advs.201600476
Franken LE, Boekema EJ. Stuart, transmission electron microscopy as a tool for the characterization of soft materials: application and interpretation. Adv Sci. 2017;4(5):1600476.10.1002/advs.201600476
56. Qian H Jia Y McCluskie MJ Application of cryogenic transmission electron microscopy for evaluation of vaccine delivery carriers Methods Mol Biol 2021 2183 499 511 10.1007/978-1-0716-0795-4_28 32959263
Qian H, Jia Y, McCluskie MJ. Application of cryogenic transmission electron microscopy for evaluation of vaccine delivery carriers. Methods Mol Biol. 2021;2183:499–511.32959263 10.1007/978-1-0716-0795-4_28
57. Lin B Hui J Mao H Nanopore technology and its applications in gene sequencing Biosensors 2021 10.3390/bios11070214 35049639
Lin B, Hui J, Mao H. Nanopore technology and its applications in gene sequencing. Biosensors. 2021. 10.3390/bios11070214.35049639 10.3390/bios11070214
58. Moore C Wing R Pham T Jokerst JV Multispectral nanoparticle tracking analysis for the real-time and label-free characterization of amyloid-β Self-assembly in vitro Anal Chem 2020 92 17 11590 11599 10.1021/acs.analchem.0c01048 32786456
Moore C, Wing R, Pham T, Jokerst JV. Multispectral nanoparticle tracking analysis for the real-time and label-free characterization of amyloid-β Self-assembly in vitro. Anal Chem. 2020;92(17):11590–9.32786456 10.1021/acs.analchem.0c01048
59. Phan TK Poon IK Atkin-Smith GK Detection and isolation of apoptotic bodies to high purity J Vis Exp 2018 10.3791/58317 30148494
Phan TK, Poon IK, Atkin-Smith GK. Detection and isolation of apoptotic bodies to high purity. J Vis Exp. 2018. 10.3791/58317.30148494 10.3791/58317
60. Atkin-Smith GK Paone S Zanker DJ Duan M Phan TK Chen W Hulett MD Poon IK Isolation of cell type-specific apoptotic bodies by fluorescence-activated cell sorting Sci Rep 2017 7 39846 10.1038/srep39846 28057919
Atkin-Smith GK, Paone S, Zanker DJ, Duan M, Phan TK, Chen W, Hulett MD, Poon IK. Isolation of cell type-specific apoptotic bodies by fluorescence-activated cell sorting. Sci Rep. 2017;7:39846.28057919 10.1038/srep39846
61. Livshits MA Khomyakova E Evtushenko EG Lazarev VN Kulemin NA Semina SE Generozov EV Govorun VM Isolation of exosomes by differential centrifugation: theoretical analysis of a commonly used protocol Sci Rep 2015 5 17319 10.1038/srep17319 26616523
Livshits MA, Khomyakova E, Evtushenko EG, Lazarev VN, Kulemin NA, Semina SE, Generozov EV, Govorun VM. Isolation of exosomes by differential centrifugation: theoretical analysis of a commonly used protocol. Sci Rep. 2015;5:17319.26616523 10.1038/srep17319
62. Jiang L Tixeira R Caruso S Atkin-Smith GK Baxter AA Paone S Hulett MD Poon IK Monitoring the progression of cell death and the disassembly of dying cells by flow cytometry Nat Protoc 2016 11 4 655 663 10.1038/nprot.2016.028 26938116
Jiang L, Tixeira R, Caruso S, Atkin-Smith GK, Baxter AA, Paone S, Hulett MD, Poon IK. Monitoring the progression of cell death and the disassembly of dying cells by flow cytometry. Nat Protoc. 2016;11(4):655–63.26938116 10.1038/nprot.2016.028
63. Meehan B Rak J Di Vizio D Oncosomes—large and small: what are they, where they came from? J Extracell Vesicles 2016 5 33109 10.3402/jev.v5.33109 27680302
Meehan B, Rak J, Di Vizio D. Oncosomes—large and small: what are they, where they came from? J Extracell Vesicles. 2016;5:33109.27680302 10.3402/jev.v5.33109
64. Santavanond JP Rutter SF Atkin-Smith GK Poon IKH Apoptotic bodies: mechanism of formation, isolation and functional relevance Subcell Biochem 2021 97 61 88 10.1007/978-3-030-67171-6_4 33779914
Santavanond JP, Rutter SF, Atkin-Smith GK, Poon IKH. Apoptotic bodies: mechanism of formation, isolation and functional relevance. Subcell Biochem. 2021;97:61–88.33779914 10.1007/978-3-030-67171-6_4
65. Atkin-Smith GK Miles MA Tixeira R Lay FT Duan M Hawkins CJ Phan TK Paone S Mathivanan S Hulett MD Chen W Poon IKH Plexin B2 is a regulator of monocyte apoptotic cell disassembly Cell Rep 2019 29 7 1821 1831.e3 10.1016/j.celrep.2019.10.014 31722200
Atkin-Smith GK, Miles MA, Tixeira R, Lay FT, Duan M, Hawkins CJ, Phan TK, Paone S, Mathivanan S, Hulett MD, Chen W, Poon IKH. Plexin B2 is a regulator of monocyte apoptotic cell disassembly. Cell Rep. 2019;29(7):1821-1831.e3.31722200 10.1016/j.celrep.2019.10.014
66. Yuan FL Wu QY Miao ZN Xu MH Xu RS Jiang DL Ye JX Chen FH Zhao MD Wang HJ Li X Osteoclast-derived extracellular vesicles: novel regulators of osteoclastogenesis and osteoclast-osteoblasts communication in bone remodeling Front Physiol 2018 9 628 10.3389/fphys.2018.00628 29910740
Yuan FL, Wu QY, Miao ZN, Xu MH, Xu RS, Jiang DL, Ye JX, Chen FH, Zhao MD, Wang HJ, Li X. Osteoclast-derived extracellular vesicles: novel regulators of osteoclastogenesis and osteoclast-osteoblasts communication in bone remodeling. Front Physiol. 2018;9:628.29910740 10.3389/fphys.2018.00628
67. Zhu Z Zhang D Lee H Menon AA Wu J Hu K Jin Y Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222 J Leukoc Biol 2017 101 6 1349 1359 10.1189/jlb.3A1116-483R 28274991
Zhu Z, Zhang D, Lee H, Menon AA, Wu J, Hu K, Jin Y. Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. J Leukoc Biol. 2017;101(6):1349–59.28274991 10.1189/jlb.3A1116-483R
68. Zhu Y Zhang X Yang K Shao Y Gu R Liu X Liu H Liu Y Zhou Y Macrophage-derived apoptotic vesicles regulate fate commitment of mesenchymal stem cells via miR155 Stem Cell Res Ther 2022 13 1 323 10.1186/s13287-022-03004-w 35842708
Zhu Y, Zhang X, Yang K, Shao Y, Gu R, Liu X, Liu H, Liu Y, Zhou Y. Macrophage-derived apoptotic vesicles regulate fate commitment of mesenchymal stem cells via miR155. Stem Cell Res Ther. 2022;13(1):323.35842708 10.1186/s13287-022-03004-w
69. Tyukavin AI Belostotskaya GB Golovanova TA Galagudza MM Zakharov EA Burkova NV Ivkin DY Karpov AA Stimulation of proliferation and differentiation of rat resident myocardial cells with apoptotic bodies of cardiomyocytes Bull Exp Biol Med 2015 159 1 138 141 10.1007/s10517-015-2909-6 26033604
Tyukavin AI, Belostotskaya GB, Golovanova TA, Galagudza MM, Zakharov EA, Burkova NV, Ivkin DY, Karpov AA. Stimulation of proliferation and differentiation of rat resident myocardial cells with apoptotic bodies of cardiomyocytes. Bull Exp Biol Med. 2015;159(1):138–41.26033604 10.1007/s10517-015-2909-6
70. Tyukavin AI Belostotskaya GB Zakharov CAC Ivkin DY Rad’ko SV Knyazev NA Klimenko VV Bogdanov AA Suchkov SV Apoptotic bodies of cardiomyocytes and fibroblasts—regulators of directed differentiation of heart stem cells Bull Exp Biol Med 2020 170 1 112 117 10.1007/s10517-020-05015-0 33237531
Tyukavin AI, Belostotskaya GB, Zakharov CAC, Ivkin DY, Rad’ko SV, Knyazev NA, Klimenko VV, Bogdanov AA, Suchkov SV. Apoptotic bodies of cardiomyocytes and fibroblasts—regulators of directed differentiation of heart stem cells. Bull Exp Biol Med. 2020;170(1):112–7.33237531 10.1007/s10517-020-05015-0
71. Morad G Carman CV Hagedorn EJ Perlin JR Zon LI Mustafaoglu N Park TE Ingber DE Daisy CC Moses MA Tumor-derived extracellular vesicles breach the intact blood-brain barrier via transcytosis ACS Nano 2019 13 12 13853 13865 10.1021/acsnano.9b04397 31479239
Morad G, Carman CV, Hagedorn EJ, Perlin JR, Zon LI, Mustafaoglu N, Park TE, Ingber DE, Daisy CC, Moses MA. Tumor-derived extracellular vesicles breach the intact blood-brain barrier via transcytosis. ACS Nano. 2019;13(12):13853–65.31479239 10.1021/acsnano.9b04397
72. Zhao D Tao W Li S Chen Y Sun Y He Z Sun B Sun J Apoptotic body-mediated intercellular delivery for enhanced drug penetration and whole tumor destruction Sci Adv 2021 10.1126/sciadv.abg0880 34936449
Zhao D, Tao W, Li S, Chen Y, Sun Y, He Z, Sun B, Sun J. Apoptotic body-mediated intercellular delivery for enhanced drug penetration and whole tumor destruction. Sci Adv. 2021. 10.1126/sciadv.abg0880.34936449 10.1126/sciadv.abg0880
73. Fazakas C Wilhelm I Nagyoszi P Farkas AE Haskó J Molnár J Bauer H Bauer HC Ayaydin F Dung NT Siklós L Krizbai IA Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases PLoS ONE 2011 6 6 e20758 10.1371/journal.pone.0020758 21674054
Fazakas C, Wilhelm I, Nagyoszi P, Farkas AE, Haskó J, Molnár J, Bauer H, Bauer HC, Ayaydin F, Dung NT, Siklós L, Krizbai IA. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE. 2011;6(6): e20758.21674054 10.1371/journal.pone.0020758
74. Jing B Guo F An R Gao Y Li Y Xie Y Wang J Chen Y Li H Gao T Jin Q Zhang L Xie M Apoptotic tumor cell-derived microparticles loading napabucasin inhibit CSCs and synergistic immune therapy J Nanobiotech 2023 21 1 37 10.1186/s12951-023-01792-8
Jing B, Guo F, An R, Gao Y, Li Y, Xie Y, Wang J, Chen Y, Li H, Gao T, Jin Q, Zhang L, Xie M. Apoptotic tumor cell-derived microparticles loading napabucasin inhibit CSCs and synergistic immune therapy. J Nanobiotech. 2023;21(1):37.10.1186/s12951-023-01792-8
75. Wang H Brown PC Chow ECY Ewart L Ferguson SS Fitzpatrick S Freedman BS Guo GL Hedrich W Heyward S Hickman J Isoherranen N Li AP Liu Q Mumenthaler SM Polli J Proctor WR Ribeiro A Wang JY Wange RL Huang SM 3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration Clin Transl Sci 2021 14 5 1659 1680 10.1111/cts.13066 33982436
Wang H, Brown PC, Chow ECY, Ewart L, Ferguson SS, Fitzpatrick S, Freedman BS, Guo GL, Hedrich W, Heyward S, Hickman J, Isoherranen N, Li AP, Liu Q, Mumenthaler SM, Polli J, Proctor WR, Ribeiro A, Wang JY, Wange RL, Huang SM. 3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration. Clin Transl Sci. 2021;14(5):1659–80.33982436 10.1111/cts.13066
76. Namgung B Ravi K Vikraman PP Sengupta S Jang HL Engineered cell-laden alginate microparticles for 3D culture Biochem Soc Trans 2021 49 2 761 773 10.1042/BST20200673 33860783
Namgung B, Ravi K, Vikraman PP, Sengupta S, Jang HL. Engineered cell-laden alginate microparticles for 3D culture. Biochem Soc Trans. 2021;49(2):761–73.33860783 10.1042/BST20200673
77. Langhans SA Using 3D in vitro cell culture models in anti-cancer drug discovery Expert Opin Drug Discov 2021 16 8 841 850 10.1080/17460441.2021.1912731 33823728
Langhans SA. Using 3D in vitro cell culture models in anti-cancer drug discovery. Expert Opin Drug Discov. 2021;16(8):841–50.33823728 10.1080/17460441.2021.1912731
78. Russo M Cejas CM Pitingolo G Advances in microfluidic 3D cell culture for preclinical drug development Prog Mol Biol Transl Sci 2022 187 1 163 204 10.1016/bs.pmbts.2021.07.022 35094774
Russo M, Cejas CM, Pitingolo G. Advances in microfluidic 3D cell culture for preclinical drug development. Prog Mol Biol Transl Sci. 2022;187(1):163–204.35094774 10.1016/bs.pmbts.2021.07.022
79. Serrano-Heras G Díaz-Maroto I Castro-Robles B Carrión B Perona-Moratalla AB Gracia J Arteaga S Hernández-Fernández F García-García J Ayo-Martín O Segura T Isolation and quantification of blood apoptotic bodies, a non-invasive tool to evaluate apoptosis in patients with ischemic stroke and neurodegenerative diseases Biol Proced Online 2020 22 17 10.1186/s12575-020-00130-8 32765191
Serrano-Heras G, Díaz-Maroto I, Castro-Robles B, Carrión B, Perona-Moratalla AB, Gracia J, Arteaga S, Hernández-Fernández F, García-García J, Ayo-Martín O, Segura T. Isolation and quantification of blood apoptotic bodies, a non-invasive tool to evaluate apoptosis in patients with ischemic stroke and neurodegenerative diseases. Biol Proced Online. 2020;22:17.32765191 10.1186/s12575-020-00130-8
80. Merchant ML Rood IM Deegens JKJ Klein JB Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery Nat Rev Nephrol 2017 13 12 731 749 10.1038/nrneph.2017.148 29081510
Merchant ML, Rood IM, Deegens JKJ, Klein JB. Isolation and characterization of urinary extracellular vesicles: implications for biomarker discovery. Nat Rev Nephrol. 2017;13(12):731–49.29081510 10.1038/nrneph.2017.148
81. Masvekar R Mizrahi J Park J Williamson PR Bielekova B Quantifications of CSF apoptotic bodies do not provide clinical value in multiple sclerosis Front Neurol 2019 10 1241 10.3389/fneur.2019.01241 31849814
Masvekar R, Mizrahi J, Park J, Williamson PR, Bielekova B. Quantifications of CSF apoptotic bodies do not provide clinical value in multiple sclerosis. Front Neurol. 2019;10:1241.31849814 10.3389/fneur.2019.01241
82. Wu X Cheng B Cai ZD Lou LM Determination of the apoptotic index in osteosarcoma tissue and its relationship with patients prognosis Cancer Cell Int 2013 13 1 56 10.1186/1475-2867-13-56 23734671
Wu X, Cheng B, Cai ZD, Lou LM. Determination of the apoptotic index in osteosarcoma tissue and its relationship with patients prognosis. Cancer Cell Int. 2013;13(1):56.23734671 10.1186/1475-2867-13-56
83. Cohen JJ Apoptosis Immunol Today 1993 14 3 126 130 10.1016/0167-5699(93)90214-6 8466628
Cohen JJ. Apoptosis. Immunol Today. 1993;14(3):126–30.8466628 10.1016/0167-5699(93)90214-6
84. Han M Ryu G Shin SA An J Kim H Park D Lee DH Lee CS Physiological roles of apoptotic cell clearance: beyond immune functions Life 2021 10.3390/life11111141 34947967
Han M, Ryu G, Shin SA, An J, Kim H, Park D, Lee DH, Lee CS. Physiological roles of apoptotic cell clearance: beyond immune functions. Life. 2021. 10.3390/life11111141.34947967 10.3390/life11111141
85. Shin SA Moon SY Park D Park JB Lee CS Apoptotic cell clearance in the tumor microenvironment: a potential cancer therapeutic target Arch Pharm Res 2019 42 8 658 671 10.1007/s12272-019-01169-2 31243646
Shin SA, Moon SY, Park D, Park JB, Lee CS. Apoptotic cell clearance in the tumor microenvironment: a potential cancer therapeutic target. Arch Pharm Res. 2019;42(8):658–71.31243646 10.1007/s12272-019-01169-2
86. Nakayama M Akiba H Takeda K Kojima Y Hashiguchi M Azuma M Yagita H Okumura K Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation Blood 2009 113 16 3821 3830 10.1182/blood-2008-10-185884 19224762
Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113(16):3821–30.19224762 10.1182/blood-2008-10-185884
87. Pontejo SM Murphy PM Chemokines act as phosphatidylserine-bound "find-me" signals in apoptotic cell clearance PLoS Biol 2021 19 5 e3001259 10.1371/journal.pbio.3001259 34038417
Pontejo SM, Murphy PM. Chemokines act as phosphatidylserine-bound “find-me” signals in apoptotic cell clearance. PLoS Biol. 2021;19(5): e3001259.34038417 10.1371/journal.pbio.3001259
88. Park SY Jung MY Kim HJ Lee SJ Kim SY Lee BH Kwon TH Park RW Kim IS Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor Cell Death Differ 2008 15 1 192 201 10.1038/sj.cdd.4402242 17962816
Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH, Kwon TH, Park RW, Kim IS. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 2008;15(1):192–201.17962816 10.1038/sj.cdd.4402242
89. Kobayashi N Karisola P Peña-Cruz V Dorfman DM Jinushi M Umetsu SE Butte MJ Nagumo H Chernova I Zhu B Sharpe AH Ito S Dranoff G Kaplan GG Casasnovas JM Umetsu DT Dekruyff RH Freeman GJ TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells Immunity 2007 27 6 927 940 10.1016/j.immuni.2007.11.011 18082433
Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity. 2007;27(6):927–40.18082433 10.1016/j.immuni.2007.11.011
90. Green DR Ferguson T Zitvogel L Kroemer G Immunogenic and tolerogenic cell death Nat Rev Immunol 2009 9 5 353 363 10.1038/nri2545 19365408
Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9(5):353–63.19365408 10.1038/nri2545
91. Park SY Jung MY Lee SJ Kang KB Gratchev A Riabov V Kzhyshkowska J Kim IS Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages J Cell Sci 2009 122 Pt 18 3365 3373 10.1242/jcs.049569 19726632
Park SY, Jung MY, Lee SJ, Kang KB, Gratchev A, Riabov V, Kzhyshkowska J, Kim IS. Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages. J Cell Sci. 2009;122(Pt 18):3365–73.19726632 10.1242/jcs.049569
92. Rodriguez-Manzanet R Sanjuan MA Wu HY Quintana FJ Xiao S Anderson AC Weiner HL Green DR Kuchroo VK T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice Proc Natl Acad Sci U S A 2010 107 19 8706 8711 10.1073/pnas.0910359107 20368430
Rodriguez-Manzanet R, Sanjuan MA, Wu HY, Quintana FJ, Xiao S, Anderson AC, Weiner HL, Green DR, Kuchroo VK. T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc Natl Acad Sci U S A. 2010;107(19):8706–11.20368430 10.1073/pnas.0910359107
93. Kelley SM Ravichandran KS Putting the brakes on phagocytosis: “don't-eat-me” signaling in physiology and disease Embo Rep 2021 10.15252/embr.202152564 34041845
Kelley SM, Ravichandran KS. Putting the brakes on phagocytosis: “don’t-eat-me” signaling in physiology and disease. Embo Rep. 2021. 10.15252/embr.202152564.34041845 10.15252/embr.202152564
94. Eguchi A Mulya A Lazic M Radhakrishnan D Berk MP Povero D Gornicka A Feldstein AE Microparticles release by adipocytes act as "find-me" signals to promote macrophage migration PLoS ONE 2015 10 4 e0123110 10.1371/journal.pone.0123110 25849214
Eguchi A, Mulya A, Lazic M, Radhakrishnan D, Berk MP, Povero D, Gornicka A, Feldstein AE. Microparticles release by adipocytes act as “find-me” signals to promote macrophage migration. PLoS ONE. 2015;10(4): e0123110.25849214 10.1371/journal.pone.0123110
95. Segundo C Medina F Rodríguez C Martínez-Palencia R Leyva-Cobián F Brieva JA Surface molecule loss and bleb formation by human germinal center B cells undergoing apoptosis: role of apoptotic blebs in monocyte chemotaxis Blood 1999 94 3 1012 1020 10.1182/blood.V94.3.1012.415k05_1012_1020 10419893
Segundo C, Medina F, Rodríguez C, Martínez-Palencia R, Leyva-Cobián F, Brieva JA. Surface molecule loss and bleb formation by human germinal center B cells undergoing apoptosis: role of apoptotic blebs in monocyte chemotaxis. Blood. 1999;94(3):1012–20.10419893 10.1182/blood.V94.3.1012.415k05_1012_1020
96. Torr EE Gardner DH Thomas L Goodall DM Bielemeier A Willetts R Griffiths HR Marshall LJ Devitt A Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells Cell Death Differ 2012 19 4 671 679 10.1038/cdd.2011.167 22117198
Torr EE, Gardner DH, Thomas L, Goodall DM, Bielemeier A, Willetts R, Griffiths HR, Marshall LJ, Devitt A. Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ. 2012;19(4):671–9.22117198 10.1038/cdd.2011.167
97. Fischer U Jänicke RU Schulze-Osthoff K Many cuts to ruin: a comprehensive update of caspase substrates Cell Death Differ 2003 10 1 76 100 10.1038/sj.cdd.4401160 12655297
Fischer U, Jänicke RU, Schulze-Osthoff K. Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ. 2003;10(1):76–100.12655297 10.1038/sj.cdd.4401160
98. Battistelli M Falcieri E Apoptotic bodies: particular extracellular vesicles involved in intercellular communication Biology 2020 10.3390/biology9010021 31968627
Battistelli M, Falcieri E. Apoptotic bodies: particular extracellular vesicles involved in intercellular communication. Biology. 2020. 10.3390/biology9010021.31968627 10.3390/biology9010021
99. Atkin-Smith GK Duan MB Zanker DJ Loh L Nguyen THO Koutsakos M Nguyen T Jiang XR Carrera J Phan TK Liu CX Paone S Oveissi S Hodge AL Baxter AA Kedzierska K Mackenzie JM Hulett MD Bilsel P Chen WS Poon IKH Monocyte apoptotic bodies are vehicles for influenza A virus propagation Commun Biol 2020 10.1038/s42003-020-0955-8 32385344
Atkin-Smith GK, Duan MB, Zanker DJ, Loh L, Nguyen THO, Koutsakos M, Nguyen T, Jiang XR, Carrera J, Phan TK, Liu CX, Paone S, Oveissi S, Hodge AL, Baxter AA, Kedzierska K, Mackenzie JM, Hulett MD, Bilsel P, Chen WS, Poon IKH. Monocyte apoptotic bodies are vehicles for influenza A virus propagation. Commun Biol. 2020. 10.1038/s42003-020-0955-8.32385344 10.1038/s42003-020-0955-8
100. Ori A Wilkinson MC Fernig DG The heparanome and regulation of cell function: structures, functions and challenges Front Biosci 2008 13 4309 4338 10.2741/3007 18508513
Ori A, Wilkinson MC, Fernig DG. The heparanome and regulation of cell function: structures, functions and challenges. Front Biosci. 2008;13:4309–38.18508513 10.2741/3007
101. Ripszky Totan A Imre MM Parvu S Meghea D Radulescu R Enasescu DSA Moisa MR Pituru SM Autophagy plays multiple roles in the soft-tissue healing and osseointegration in dental implant surgery-a narrative review Materials 2022 10.3390/ma15176041 36079421
Ripszky Totan A, Imre MM, Parvu S, Meghea D, Radulescu R, Enasescu DSA, Moisa MR, Pituru SM. Autophagy plays multiple roles in the soft-tissue healing and osseointegration in dental implant surgery-a narrative review. Materials. 2022. 10.3390/ma15176041.36079421 10.3390/ma15176041
102. Tan A Prasad R Lee C Jho EH Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease Cell Death Differ 2022 29 8 1433 1449 10.1038/s41418-022-01028-6 35739255
Tan A, Prasad R, Lee C, Jho EH. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease. Cell Death Differ. 2022;29(8):1433–49.35739255 10.1038/s41418-022-01028-6
103. Thorburn A Apoptosis and autophagy: regulatory connections between two supposedly different processes Apoptosis 2008 13 1 1 9 10.1007/s10495-007-0154-9 17990121
Thorburn A. Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis. 2008;13(1):1–9.17990121 10.1007/s10495-007-0154-9
104. Xi H Wang S Wang B Hong X Liu X Li M Shen R Dong Q The role of interaction between autophagy and apoptosis in tumorigenesis (Review) Oncol Rep 2022 48 6 208 10.3892/or.2022.8423 36222296
Xi H, Wang S, Wang B, Hong X, Liu X, Li M, Shen R, Dong Q. The role of interaction between autophagy and apoptosis in tumorigenesis (Review). Oncol Rep. 2022;48(6):208.36222296 10.3892/or.2022.8423
105. Li M Gao P Zhang J Crosstalk between autophagy and apoptosis: potential and emerging therapeutic targets for cardiac diseases Int J Mol Sci 2016 17 3 332 10.3390/ijms17030332 26950124
Li M, Gao P, Zhang J. Crosstalk between autophagy and apoptosis: potential and emerging therapeutic targets for cardiac diseases. Int J Mol Sci. 2016;17(3):332.26950124 10.3390/ijms17030332
106. He C Xu Y Sun J Li L Zhang JH Wang Y Autophagy and apoptosis in acute brain injuries: from mechanism to treatment Antioxid Redox Signal 2023 38 1–3 234 257 10.1089/ars.2021.0094 35579958
He C, Xu Y, Sun J, Li L, Zhang JH, Wang Y. Autophagy and apoptosis in acute brain injuries: from mechanism to treatment. Antioxid Redox Signal. 2023;38(1–3):234–57.35579958 10.1089/ars.2021.0094
107. Khachigian LM Black BL Ferdinandy P De Caterina R Madonna R Geng Y-J Transcriptional regulation of vascular smooth muscle cell proliferation, differentiation and senescence: novel targets for therapy Vascul Pharmacol 2022 146 107091 10.1016/j.vph.2022.107091 35896140
Khachigian LM, Black BL, Ferdinandy P, De Caterina R, Madonna R, Geng Y-J. Transcriptional regulation of vascular smooth muscle cell proliferation, differentiation and senescence: novel targets for therapy. Vascul Pharmacol. 2022;146: 107091.35896140 10.1016/j.vph.2022.107091
108. Calabrese EJ Hormesis and bone marrow stem cells: enhancing cell proliferation, differentiation and resilience to inflammatory stress Chem Biol Interact 2022 351 109730 10.1016/j.cbi.2021.109730 34728189
Calabrese EJ. Hormesis and bone marrow stem cells: enhancing cell proliferation, differentiation and resilience to inflammatory stress. Chem Biol Interact. 2022;351: 109730.34728189 10.1016/j.cbi.2021.109730
109. Lee K Gusella GL He JC Epithelial proliferation and cell cycle dysregulation in kidney injury and disease Kidney Int 2021 100 1 67 78 10.1016/j.kint.2021.03.024 33831367
Lee K, Gusella GL, He JC. Epithelial proliferation and cell cycle dysregulation in kidney injury and disease. Kidney Int. 2021;100(1):67–78.33831367 10.1016/j.kint.2021.03.024
110. Sever D Grapin-Botton A Regeneration of the pancreas: proliferation and cellular conversion of surviving cells Curr Opin Genet Dev 2020 64 84 93 10.1016/j.gde.2020.06.005 32721583
Sever D, Grapin-Botton A. Regeneration of the pancreas: proliferation and cellular conversion of surviving cells. Curr Opin Genet Dev. 2020;64:84–93.32721583 10.1016/j.gde.2020.06.005
111. Dong C Gingery A Amadio PC An KN Moran SL Zhao C Apoptotic body-rich media from tenocytes enhance proliferation and migration of tenocytes and bone marrow stromal cells Int J Mol Sci 2022 23 19 11475 10.3390/ijms231911475 36232777
Dong C, Gingery A, Amadio PC, An KN, Moran SL, Zhao C. Apoptotic body-rich media from tenocytes enhance proliferation and migration of tenocytes and bone marrow stromal cells. Int J Mol Sci. 2022;23(19):11475.36232777 10.3390/ijms231911475
112. Jiang L Lu J Chen Y Lyu K Long L Wang X Liu T Li S Mesenchymal stem cells: an efficient cell therapy for tendon repair (Review) Int J Mol Med 2023 52 2 70 10.3892/ijmm.2023.5273 37387410
Jiang L, Lu J, Chen Y, Lyu K, Long L, Wang X, Liu T, Li S. Mesenchymal stem cells: an efficient cell therapy for tendon repair (Review). Int J Mol Med. 2023;52(2):70.37387410 10.3892/ijmm.2023.5273
113. Song J EMT or apoptosis: a decision for TGF-beta Cell Res 2007 17 4 289 290 10.1038/cr.2007.25 17426696
Song J. EMT or apoptosis: a decision for TGF-beta. Cell Res. 2007;17(4):289–90.17426696 10.1038/cr.2007.25
114. Hossain M Shim R Lee WY Sharpe AH Kubes P Gata6(+) resident peritoneal macrophages promote the growth of liver metastasis Nat Commun 2022 13 1 4406 10.1038/s41467-022-32080-y 35906202
Hossain M, Shim R, Lee WY, Sharpe AH, Kubes P. Gata6(+) resident peritoneal macrophages promote the growth of liver metastasis. Nat Commun. 2022;13(1):4406.35906202 10.1038/s41467-022-32080-y
115. Sun CY Cao D Du BB Chen CW Liu D The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m(6)A readers in cancer Int J Biol Sci 2022 18 7 2744 2758 10.7150/ijbs.70458 35541906
Sun CY, Cao D, Du BB, Chen CW, Liu D. The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m(6)A readers in cancer. Int J Biol Sci. 2022;18(7):2744–58.35541906 10.7150/ijbs.70458
116. Nowosad A Besson A CDKN1B/p27 regulates autophagy via the control of ragulator and MTOR activity in amino acid-deprived cells Autophagy 2020 16 12 2297 2298 10.1080/15548627.2020.1831217 33016184
Nowosad A, Besson A. CDKN1B/p27 regulates autophagy via the control of ragulator and MTOR activity in amino acid-deprived cells. Autophagy. 2020;16(12):2297–8.33016184 10.1080/15548627.2020.1831217
117. Hristov M Erl W Linder S Weber PC Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro Blood 2004 104 9 2761 2766 10.1182/blood-2003-10-3614 15242875
Hristov M, Erl W, Linder S, Weber PC. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood. 2004;104(9):2761–6.15242875 10.1182/blood-2003-10-3614
118. Krentz NAJ Improvements in stem cell to beta-cell differentiation for the treatment of diabetes J Immunol Reg Med 2021 12 100043
Krentz NAJ. Improvements in stem cell to beta-cell differentiation for the treatment of diabetes. J Immunol Reg Med. 2021;12: 100043.
119. Montazersaheb S Fathi E Farahzadi R Cytokines and signaling pathways involved in differentiation potential of hematopoietic stem cells towards natural killer cells Tissue Cell 2021 70 101501 10.1016/j.tice.2021.101501 33578272
Montazersaheb S, Fathi E, Farahzadi R. Cytokines and signaling pathways involved in differentiation potential of hematopoietic stem cells towards natural killer cells. Tissue Cell. 2021;70: 101501.33578272 10.1016/j.tice.2021.101501
120. Yarahmadi HB Khani A Baghdadchi Y Javadi M Sharafi A Sohi AN Kheiri HR Study of the biological relevance of Wnt/β-catenin signaling pathway and β-adrenergic regulation in osteoblastic differentiation of mesenchymal stem cells Gene Reports 2022 29 101662 10.1016/j.genrep.2022.101662
Yarahmadi HB, Khani A, Baghdadchi Y, Javadi M, Sharafi A, Sohi AN, Kheiri HR. Study of the biological relevance of Wnt/β-catenin signaling pathway and β-adrenergic regulation in osteoblastic differentiation of mesenchymal stem cells. Gene Reports. 2022;29: 101662.10.1016/j.genrep.2022.101662
121. Zhou Z Hossain MS Liu D Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration Stem Cell Res Thera 2021 10.1186/s13287-021-02149-4
Zhou Z, Hossain MS, Liu D. Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration. Stem Cell Res Thera. 2021. 10.1186/s13287-021-02149-4.10.1186/s13287-021-02149-4
122. Shen G Ren H Qiu T Zhang Z Zhao W Yu X Huang J Tang J Liang D Yao Z Yang Z Jiang X Mammalian target of rapamycin as a therapeutic target in osteoporosis J Cell Physiol 2018 233 5 3929 3944 10.1002/jcp.26161 28834576
Shen G, Ren H, Qiu T, Zhang Z, Zhao W, Yu X, Huang J, Tang J, Liang D, Yao Z, Yang Z, Jiang X. Mammalian target of rapamycin as a therapeutic target in osteoporosis. J Cell Physiol. 2018;233(5):3929–44.28834576 10.1002/jcp.26161
123. Thomson BM Mundy GR Chambers TJ Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption J Immunol 1987 138 3 775 779 10.4049/jimmunol.138.3.775 3805716
Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol. 1987;138(3):775–9.3805716 10.4049/jimmunol.138.3.775
124. Bertolini DR Nedwin GE Bringman TS Smith DD Mundy GR Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors Nature 1986 319 6053 516 518 10.1038/319516a0 3511389
Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986;319(6053):516–8.3511389 10.1038/319516a0
125. Marin-Gallen S Clemente-Casares X Planas R Pujol-Autonell I Carrascal J Carrillo J Ampudia R Verdaguer J Pujol-Borrell R Borràs FE Vives-Pi M Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes Clin Exp Immunol 2010 160 2 207 214 10.1111/j.1365-2249.2009.04082.x 20030670
Marin-Gallen S, Clemente-Casares X, Planas R, Pujol-Autonell I, Carrascal J, Carrillo J, Ampudia R, Verdaguer J, Pujol-Borrell R, Borràs FE, Vives-Pi M. Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes. Clin Exp Immunol. 2010;160(2):207–14.20030670 10.1111/j.1365-2249.2009.04082.x
126. Berda-Haddad Y Robert S Salers P Zekraoui L Farnarier C Dinarello CA Dignat-George F Kaplanski G Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α Proc Natl Acad Sci U S A 2011 108 51 20684 20689 10.1073/pnas.1116848108 22143786
Berda-Haddad Y, Robert S, Salers P, Zekraoui L, Farnarier C, Dinarello CA, Dignat-George F, Kaplanski G. Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α. Proc Natl Acad Sci U S A. 2011;108(51):20684–9.22143786 10.1073/pnas.1116848108
127. Rock KL Latz E Ontiveros F Kono H The sterile inflammatory response Annu Rev Immunol 2010 28 321 342 10.1146/annurev-immunol-030409-101311 20307211
Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol. 2010;28:321–42.20307211 10.1146/annurev-immunol-030409-101311
128. Dou G Tian R Liu X Yuan P Ye Q Liu J Liu S Zhou J Deng Z Chen X Liu S Jin Y Chimeric apoptotic bodies functionalized with natural membrane and modular delivery system for inflammation modulation Sci Adv 2020 10.1126/sciadv.aba2987 33310856
Dou G, Tian R, Liu X, Yuan P, Ye Q, Liu J, Liu S, Zhou J, Deng Z, Chen X, Liu S, Jin Y. Chimeric apoptotic bodies functionalized with natural membrane and modular delivery system for inflammation modulation. Sci Adv. 2020. 10.1126/sciadv.aba2987.33310856 10.1126/sciadv.aba2987
129. Honrado C Adair SJ Moore JH Salahi A Bauer TW Swami NS Apoptotic bodies in the pancreatic tumor cell culture media enable label-free drug sensitivity assessment by impedance cytometry Adv Biol (Weinh) 2021 5 8 e2100438 10.1002/adbi.202100438 34015194
Honrado C, Adair SJ, Moore JH, Salahi A, Bauer TW, Swami NS. Apoptotic bodies in the pancreatic tumor cell culture media enable label-free drug sensitivity assessment by impedance cytometry. Adv Biol (Weinh). 2021;5(8): e2100438.34015194 10.1002/adbi.202100438
130. Faridnia R Kalani H Hezarjaribi HZ Denny PW Rafie A Fakhar M Virgilio S Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination Microb Pathog 2020 147 104406 10.1016/j.micpath.2020.104406 32738284
Faridnia R, Kalani H, Hezarjaribi HZ, Denny PW, Rafie A, Fakhar M, Virgilio S. Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination. Microb Pathog. 2020;147: 104406.32738284 10.1016/j.micpath.2020.104406
131. Palma M Hansson L Choudhury A Näsman-Glaser B Eriksson I Adamson L Rossmann E Widén K Horváth R Kokhaei P Vertuani S Mellstedt H Osterborg A Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria Cancer Immunol 2012 61 6 865 879 10.1007/s00262-011-1149-5
Palma M, Hansson L, Choudhury A, Näsman-Glaser B, Eriksson I, Adamson L, Rossmann E, Widén K, Horváth R, Kokhaei P, Vertuani S, Mellstedt H, Osterborg A. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol. 2012;61(6):865–79.10.1007/s00262-011-1149-5
132. Zhao G Liu H Wang Z Yang H Zhao H Zhang Y Ge K Wang X Luo L Zhou X Zhang J Li Z Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body vaccination Acta Biomater 2022 153 529 539 10.1016/j.actbio.2022.09.014 36113726
Zhao G, Liu H, Wang Z, Yang H, Zhao H, Zhang Y, Ge K, Wang X, Luo L, Zhou X, Zhang J, Li Z. Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body vaccination. Acta Biomater. 2022;153:529–39.36113726 10.1016/j.actbio.2022.09.014
133. Wu Y Zhang Y Dai L Wang Q Xue L Su Z Zhang C An apoptotic body-biomimic liposome in situ upregulates anti-inflammatory macrophages for stabilization of atherosclerotic plaques J Control Release 2019 316 236 249 10.1016/j.jconrel.2019.10.043 31672624
Wu Y, Zhang Y, Dai L, Wang Q, Xue L, Su Z, Zhang C. An apoptotic body-biomimic liposome in situ upregulates anti-inflammatory macrophages for stabilization of atherosclerotic plaques. J Control Release. 2019;316:236–49.31672624 10.1016/j.jconrel.2019.10.043
134. Xin L Wei C Tong X Dai Y Huang D Chen J Ma L Zhang S In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: a therapy for intrauterine adhesions Bioact Mater 2022 12 107 119 35087967
Xin L, Wei C, Tong X, Dai Y, Huang D, Chen J, Ma L, Zhang S. In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: a therapy for intrauterine adhesions. Bioact Mater. 2022;12:107–19.35087967
135. Syed FZ Type 1 diabetes mellitus Ann Intern Med 2022 10.7326/AITC202203150 35500258
Syed FZ. Type 1 diabetes mellitus. Ann Intern Med. 2022. 10.7326/AITC202203150.35500258 10.7326/AITC202203150
136. Lu S Liang Q Huang Y Meng F Liu J Definition and review on a category of long non-coding RNA: atherosclerosis-associated circulating lncRNA (ASCLncRNA) PeerJ 2020 8 e10001 10.7717/peerj.10001 33240586
Lu S, Liang Q, Huang Y, Meng F, Liu J. Definition and review on a category of long non-coding RNA: atherosclerosis-associated circulating lncRNA (ASCLncRNA). PeerJ. 2020;8: e10001.33240586 10.7717/peerj.10001
137. Mir R Elfaki I Khullar N Waza AA Jha C Mir MM Nisa S Mohammad B Mir TA Maqbool M Barnawi J Albalawi SO Abu-Duhier FM Role of Selected miRNAs as diagnostic and prognostic biomarkers in cardiovascular diseases, including coronary artery disease, myocardial infarction and atherosclerosis J Cardiovasc Dev Dis 2021 8 2 22 33669699
Mir R, Elfaki I, Khullar N, Waza AA, Jha C, Mir MM, Nisa S, Mohammad B, Mir TA, Maqbool M, Barnawi J, Albalawi SO, Abu-Duhier FM. Role of Selected miRNAs as diagnostic and prognostic biomarkers in cardiovascular diseases, including coronary artery disease, myocardial infarction and atherosclerosis. J Cardiovasc Dev Dis. 2021;8(2):22.33669699
138. Hromadnikova I Kotlabova K Krofta L Hron F Follow-up of gestational trophoblastic disease/neoplasia via quantification of circulating nucleic acids of placental origin using C19MC microRNAs, hypermethylated RASSF1A, and SRY sequences Tumour Biol 2017 39 4 1010428317697548 10.1177/1010428317697548 28381180
Hromadnikova I, Kotlabova K, Krofta L, Hron F. Follow-up of gestational trophoblastic disease/neoplasia via quantification of circulating nucleic acids of placental origin using C19MC microRNAs, hypermethylated RASSF1A, and SRY sequences. Tumour Biol. 2017;39(4):1010428317697548.28381180 10.1177/1010428317697548
139. Sarfi M Abbastabar M Khalili E Long noncoding RNAs biomarker-based cancer assessment J Cell Physiol 2019 234 10 16971 16986 10.1002/jcp.28417 30835829
Sarfi M, Abbastabar M, Khalili E. Long noncoding RNAs biomarker-based cancer assessment. J Cell Physiol. 2019;234(10):16971–86.30835829 10.1002/jcp.28417
140. Lin J Fan R Zhao Z Cummings OW Chen S Is the presence of 6 or fewer crypt apoptotic bodies sufficient for diagnosis of graft versus host disease? a decade of experience at a single institution Am J Surg Pathol 2013 37 4 539 547 10.1097/PAS.0b013e318272c62a 23211294
Lin J, Fan R, Zhao Z, Cummings OW, Chen S. Is the presence of 6 or fewer crypt apoptotic bodies sufficient for diagnosis of graft versus host disease? a decade of experience at a single institution. Am J Surg Pathol. 2013;37(4):539–47.23211294 10.1097/PAS.0b013e318272c62a
141. Ruiz P Takahashi H Delacruz V Island E Selvaggi G Nishida S Moon J Smith L Asaoka T Levi D Tekin A Tzakis AG International grading scheme for acute cellular rejection in small-bowel transplantation: single-center experience Transplant Proc 2010 42 1 47 53 10.1016/j.transproceed.2009.12.026 20172279
Ruiz P, Takahashi H, Delacruz V, Island E, Selvaggi G, Nishida S, Moon J, Smith L, Asaoka T, Levi D, Tekin A, Tzakis AG. International grading scheme for acute cellular rejection in small-bowel transplantation: single-center experience. Transplant Proc. 2010;42(1):47–53.20172279 10.1016/j.transproceed.2009.12.026
142. González IA Linn R Clinicopathologic characterization of gallbladder graft-versus-host disease in the pediatric population Hum Pathol 2023 139 9 16 10.1016/j.humpath.2023.06.006 37364823
González IA, Linn R. Clinicopathologic characterization of gallbladder graft-versus-host disease in the pediatric population. Hum Pathol. 2023;139:9–16.37364823 10.1016/j.humpath.2023.06.006
143. Ono Y Gonzalez RS Apoptosis, crypt dropout, and equivocal immunohistochemical staining may indicate cytomegalovirus infection in inflammatory bowel disease patients Am J Surg Pathol 2023 47 8 933 941 10.1097/PAS.0000000000002071 37326315
Ono Y, Gonzalez RS. Apoptosis, crypt dropout, and equivocal immunohistochemical staining may indicate cytomegalovirus infection in inflammatory bowel disease patients. Am J Surg Pathol. 2023;47(8):933–41.37326315 10.1097/PAS.0000000000002071
144. Ruiz P Bagni A Brown R Cortina G Harpaz N Magid MS Reyes J Histological criteria for the identification of acute cellular rejection in human small bowel allografts: results of the pathology workshop at the VIII international small bowel transplant symposium Transplant Proc 2004 36 2 335 337 10.1016/j.transproceed.2004.01.079 15050150
Ruiz P, Bagni A, Brown R, Cortina G, Harpaz N, Magid MS, Reyes J. Histological criteria for the identification of acute cellular rejection in human small bowel allografts: results of the pathology workshop at the VIII international small bowel transplant symposium. Transplant Proc. 2004;36(2):335–7.15050150 10.1016/j.transproceed.2004.01.079
145. Sung D Iuga AC Kato T Martinez M Remotti HE Lagana SM Crypt apoptotic body counts in normal ileal biopsies overlap with graft-versus-host disease and acute cellular rejection of small bowel allografts Hum Pathol 2016 56 89 92 10.1016/j.humpath.2016.05.017 27246175
Sung D, Iuga AC, Kato T, Martinez M, Remotti HE, Lagana SM. Crypt apoptotic body counts in normal ileal biopsies overlap with graft-versus-host disease and acute cellular rejection of small bowel allografts. Hum Pathol. 2016;56:89–92.27246175 10.1016/j.humpath.2016.05.017
146. Tsuruyama T Okamoto S Fujimoto Y Yoshizawa A Yoshitoshi E Egawa H Nakase H Aini W Miyao M Tamaki K Yamabe H Haga H Uemoto S Histology of intestinal allografts: lymphocyte apoptosis and phagocytosis of lymphocytic apoptotic bodies are diagnostic findings of acute rejection in addition to crypt apoptosis Am J Surg Pathol 2013 37 2 178 184 10.1097/PAS.0b013e31826393fe 23026933
Tsuruyama T, Okamoto S, Fujimoto Y, Yoshizawa A, Yoshitoshi E, Egawa H, Nakase H, Aini W, Miyao M, Tamaki K, Yamabe H, Haga H, Uemoto S. Histology of intestinal allografts: lymphocyte apoptosis and phagocytosis of lymphocytic apoptotic bodies are diagnostic findings of acute rejection in addition to crypt apoptosis. Am J Surg Pathol. 2013;37(2):178–84.23026933 10.1097/PAS.0b013e31826393fe
147. Yousefi M Naderi NJ Muhammadnejad A Comparison of apoptotic bodies' count & mitotic index in oral squamous cell carcinoma with regional lymph node involvement Indian J Med Res 2023 157 4 311 315
Yousefi M, Naderi NJ, Muhammadnejad A. Comparison of apoptotic bodies’ count & mitotic index in oral squamous cell carcinoma with regional lymph node involvement Indian. J Med Res. 2023;157(4):311–5.
148. Franceschini T Vasuri F Muratori P Muratori L Guido M Lenzi M D'Errico A A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center Virchows Arch 2021 479 5 937 945 10.1007/s00428-021-03122-5 34189631
Franceschini T, Vasuri F, Muratori P, Muratori L, Guido M, Lenzi M, D’Errico A. A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center. Virchows Arch. 2021;479(5):937–45.34189631 10.1007/s00428-021-03122-5
149. Li RF Gupta M McCluggage WG Ronnett BM Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature Am J Surg Pathol 2013 37 3 344 355 10.1097/PAS.0b013e31826e0271 23348207
Li RF, Gupta M, McCluggage WG, Ronnett BM. Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. Am J Surg Pathol. 2013;37(3):344–55.23348207 10.1097/PAS.0b013e31826e0271
150. Zhuang Y Cheng M Li M Cui J Huang J Zhang C Si J Lin K Yu H Small extracellular vesicles derived from hypoxic mesenchymal stem cells promote vascularized bone regeneration through the miR-210-3p/EFNA3/PI3K pathway Acta Biomater 2022 150 413 426 10.1016/j.actbio.2022.07.015 35850484
Zhuang Y, Cheng M, Li M, Cui J, Huang J, Zhang C, Si J, Lin K, Yu H. Small extracellular vesicles derived from hypoxic mesenchymal stem cells promote vascularized bone regeneration through the miR-210-3p/EFNA3/PI3K pathway. Acta Biomater. 2022;150:413–26.35850484 10.1016/j.actbio.2022.07.015
151. Qin L Yang J Su X Xilan L Lei Y Dong L Chen H Chen C Zhao C Zhang H Deng J Hu N Huang W The miR-21-5p enriched in the apoptotic bodies of M2 macrophage-derived extracellular vesicles alleviates osteoarthritis by changing macrophage phenotype Genes Dis 2023 10 3 1114 1129 10.1016/j.gendis.2022.09.010 37396516
Qin L, Yang J, Su X, Xilan L, Lei Y, Dong L, Chen H, Chen C, Zhao C, Zhang H, Deng J, Hu N, Huang W. The miR-21-5p enriched in the apoptotic bodies of M2 macrophage-derived extracellular vesicles alleviates osteoarthritis by changing macrophage phenotype. Genes Dis. 2023;10(3):1114–29.37396516 10.1016/j.gendis.2022.09.010
152. Hurley DL Khosla S Update on primary osteoporosis Mayo Clin Proc 1997 72 10 943 949 10.1016/S0025-6196(11)63367-3 9379699
Hurley DL, Khosla S. Update on primary osteoporosis. Mayo Clin Proc. 1997;72(10):943–9.9379699 10.1016/S0025-6196(11)63367-3
153. Kalyanaraman H Ramdani G Joshua J Schall N Boss GR Cory E Sah RL Casteel DE Pilz RB Novel A Direct no donor regulates osteoblast and osteoclast functions and increases bone mass in ovariectomized mice J Bone Miner Res 2017 32 1 46 59 10.1002/jbmr.2909 27391172
Kalyanaraman H, Ramdani G, Joshua J, Schall N, Boss GR, Cory E, Sah RL, Casteel DE, Pilz RB, Novel A. Direct no donor regulates osteoblast and osteoclast functions and increases bone mass in ovariectomized mice. J Bone Miner Res. 2017;32(1):46–59.27391172 10.1002/jbmr.2909
154. Talbott HE Mascharak S Griffin M Wan DC Longaker MT Wound healing, fibroblast heterogeneity, and fibrosis Cell Stem Cell 2022 29 8 1161 1180 10.1016/j.stem.2022.07.006 35931028
Talbott HE, Mascharak S, Griffin M, Wan DC, Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022;29(8):1161–80.35931028 10.1016/j.stem.2022.07.006
155. Liu S Jiang L Li H Shi H Luo H Zhang Y Yu C Jin Y Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis J Invest Dermatol 2014 134 10 2648 2657 10.1038/jid.2014.169 24714203
Liu S, Jiang L, Li H, Shi H, Luo H, Zhang Y, Yu C, Jin Y. Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis. J Invest Dermatol. 2014;134(10):2648–57.24714203 10.1038/jid.2014.169
156. Pelizzo G Avanzini MA Icaro Cornaglia A Osti M Romano P Avolio L Maccario R Dominici M De Silvestri A Andreatta E Costanzo F Mantelli M Ingo D Piccinno S Calcaterra V Mesenchymal stromal cells for cutaneous wound healing in a rabbit model: pre-clinical study applicable in the pediatric surgical setting J Transl Med 2015 10.1186/s12967-015-0580-3 26152232
Pelizzo G, Avanzini MA, Icaro Cornaglia A, Osti M, Romano P, Avolio L, Maccario R, Dominici M, De Silvestri A, Andreatta E, Costanzo F, Mantelli M, Ingo D, Piccinno S, Calcaterra V. Mesenchymal stromal cells for cutaneous wound healing in a rabbit model: pre-clinical study applicable in the pediatric surgical setting. J Transl Med. 2015. 10.1186/s12967-015-0580-3.26152232 10.1186/s12967-015-0580-3
157. Murphy KC Whitehead J Falahee PC Zhou D Simon SI Leach JK Multifactorial experimental design to optimize the anti-inflammatory and proangiogenic potential of mesenchymal stem cell spheroids Stem Cells 2017 35 6 1493 1504 10.1002/stem.2606 28276602
Murphy KC, Whitehead J, Falahee PC, Zhou D, Simon SI, Leach JK. Multifactorial experimental design to optimize the anti-inflammatory and proangiogenic potential of mesenchymal stem cell spheroids. Stem Cells. 2017;35(6):1493–504.28276602 10.1002/stem.2606
158. Amini A Pouriran R Abdollahifar MA Abbaszadeh HA Ghoreishi SK Chien S Bayat M Stereological and molecular studies on the combined effects of photobiomodulation and human bone marrow mesenchymal stem cell conditioned medium on wound healing in diabetic rats J Photochem Photobiol B 2018 182 42 51 10.1016/j.jphotobiol.2018.03.010 29604553
Amini A, Pouriran R, Abdollahifar MA, Abbaszadeh HA, Ghoreishi SK, Chien S, Bayat M. Stereological and molecular studies on the combined effects of photobiomodulation and human bone marrow mesenchymal stem cell conditioned medium on wound healing in diabetic rats. J Photochem Photobiol B. 2018;182:42–51.29604553 10.1016/j.jphotobiol.2018.03.010
159. Liu Y Wang J Zhang J Marbach S Xu W Zhu L Targeting tumor-associated macrophages by mmp2-sensitive apoptotic body-mimicking nanoparticles ACS Appl Mater Interfaces 2020 12 47 52402 52414 10.1021/acsami.0c15983 33169982
Liu Y, Wang J, Zhang J, Marbach S, Xu W, Zhu L. Targeting tumor-associated macrophages by mmp2-sensitive apoptotic body-mimicking nanoparticles. ACS Appl Mater Interfaces. 2020;12(47):52402–14.33169982 10.1021/acsami.0c15983
160. Guo S Wang Y Miao L Xu Z Lin CM Zhang Y Huang L Lipid-coated cisplatin nanoparticles induce neighboring effect and exhibit enhanced anticancer efficacy ACS Nano 2013 7 11 9896 9904 10.1021/nn403606m 24083505
Guo S, Wang Y, Miao L, Xu Z, Lin CM, Zhang Y, Huang L. Lipid-coated cisplatin nanoparticles induce neighboring effect and exhibit enhanced anticancer efficacy. ACS Nano. 2013;7(11):9896–904.24083505 10.1021/nn403606m
161. Egeblad M Werb Z New functions for the matrix metalloproteinases in cancer progression Nat Rev Cancer 2002 2 3 161 174 10.1038/nrc745 11990853
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.11990853 10.1038/nrc745
162. Terstappen GC Meyer AH Bell RD Zhang W Strategies for delivering therapeutics across the blood-brain barrier Nat Rev Drug Discov 2021 20 5 362 383 10.1038/s41573-021-00139-y 33649582
Terstappen GC, Meyer AH, Bell RD, Zhang W. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov. 2021;20(5):362–83.33649582 10.1038/s41573-021-00139-y
163. Liu Y Hu D Gao D Gong P Zheng H Sun M Sheng Z Engineered apoptotic bodies hitchhiking across the blood-brain barrier achieved a combined photothermal-chemotherapeutic effect against glioma Theranostics 2023 13 9 2966 2978 10.7150/thno.80632 37284458
Liu Y, Hu D, Gao D, Gong P, Zheng H, Sun M, Sheng Z. Engineered apoptotic bodies hitchhiking across the blood-brain barrier achieved a combined photothermal-chemotherapeutic effect against glioma. Theranostics. 2023;13(9):2966–78.37284458 10.7150/thno.80632
164. Gordon SR Maute RL Dulken BW Hutter G George BM McCracken MN Gupta R Tsai JM Sinha R Corey D Ring AM Connolly AJ Weissman IL PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity Nature 2017 545 7655 495 499 10.1038/nature22396 28514441
Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, Gupta R, Tsai JM, Sinha R, Corey D, Ring AM, Connolly AJ, Weissman IL. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545(7655):495–9.28514441 10.1038/nature22396
165. Amarilyo G Iikuni N Liu A Matarese G La Cava A Leptin enhances availability of apoptotic cell-derived self-antigen in systemic lupus erythematosus PLoS ONE 2014 9 11 e112826 10.1371/journal.pone.0112826 25401752
Amarilyo G, Iikuni N, Liu A, Matarese G, La Cava A. Leptin enhances availability of apoptotic cell-derived self-antigen in systemic lupus erythematosus. PLoS ONE. 2014;9(11): e112826.25401752 10.1371/journal.pone.0112826
166. Sachdeva R Pal R A pregnancy hormone-cell death link promotes enhanced lupus-specific immunological effects Front Immunol 2022 13 1051779 10.3389/fimmu.2022.1051779 36505418
Sachdeva R, Pal R. A pregnancy hormone-cell death link promotes enhanced lupus-specific immunological effects. Front Immunol. 2022;13:1051779.36505418 10.3389/fimmu.2022.1051779
167. Cheraghipour K Shariati L Khanahmad H Ganjalikhani-Hakemi M Moridnia A Mirian M Pestehchian N Induction of apoptosis in toxoplasma gondii infected hela cells by cisplatin and sodium azide and isolation of apoptotic bodies and potential use for vaccination against toxoplasma gondii Iran J Parasitol 2018 13 3 406 415 30483332
Cheraghipour K, Shariati L, Khanahmad H, Ganjalikhani-Hakemi M, Moridnia A, Mirian M, Pestehchian N. Induction of apoptosis in toxoplasma gondii infected hela cells by cisplatin and sodium azide and isolation of apoptotic bodies and potential use for vaccination against toxoplasma gondii. Iran J Parasitol. 2018;13(3):406–15.30483332
168. Peng Y Martin DA Kenkel J Zhang K Ogden CA Elkon KB Innate and adaptive immune response to apoptotic cells J Autoimmun 2007 29 4 303 309 10.1016/j.jaut.2007.07.017 17888627
Peng Y, Martin DA, Kenkel J, Zhang K, Ogden CA, Elkon KB. Innate and adaptive immune response to apoptotic cells. J Autoimmun. 2007;29(4):303–9.17888627 10.1016/j.jaut.2007.07.017
169. Thammasri K Rauhamäki S Wang L Filippou A Kivovich V Marjomäki V Naides SJ Gilbert L Human parvovirus B19 induced apoptotic bodies contain altered self-antigens that are phagocytosed by antigen presenting cells PLoS ONE 2013 8 6 e67179 10.1371/journal.pone.0067179 23776709
Thammasri K, Rauhamäki S, Wang L, Filippou A, Kivovich V, Marjomäki V, Naides SJ, Gilbert L. Human parvovirus B19 induced apoptotic bodies contain altered self-antigens that are phagocytosed by antigen presenting cells. PLoS ONE. 2013;8(6): e67179.23776709 10.1371/journal.pone.0067179
170. Dutta P Courties G Wei Y Leuschner F Gorbatov R Robbins CS Iwamoto Y Thompson B Carlson AL Heidt T Majmudar MD Lasitschka F Etzrodt M Waterman P Waring MT Chicoine AT van der Laan AM Niessen HW Piek JJ Rubin BB Butany J Stone JR Katus HA Murphy SA Morrow DA Sabatine MS Vinegoni C Moskowitz MA Pittet MJ Libby P Lin CP Swirski FK Weissleder R Nahrendorf M Myocardial infarction accelerates atherosclerosis Nature 2012 487 7407 325 329 10.1038/nature11260 22763456
Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487(7407):325–9.22763456 10.1038/nature11260
171. Kubyshkin A Tyukavin A Mykhaylichenko V Fomochkina I Multipotent mesenchymal bone marrow-derived stem cells and apoptotic bodies of cardiomyocytes in process of myocardium reparative morphogenesis Pathophysiology 2018 25 3 159 10.1016/j.pathophys.2018.07.006
Kubyshkin A, Tyukavin A, Mykhaylichenko V, Fomochkina I. Multipotent mesenchymal bone marrow-derived stem cells and apoptotic bodies of cardiomyocytes in process of myocardium reparative morphogenesis. Pathophysiology. 2018;25(3):159.10.1016/j.pathophys.2018.07.006
172. Brieler J Breeden MA Tucker J Cardiomyopathy: an overview Am Fam Physician 2017 96 10 640 646 29431384
Brieler J, Breeden MA, Tucker J. Cardiomyopathy: an overview. Am Fam Physician. 2017;96(10):640–6.29431384
173. Hongo D Tang X Zhang X Engleman EG Strober S Tolerogenic interactions between CD8(+) dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts Blood 2017 129 12 1718 1728 10.1182/blood-2016-07-723015 28096089
Hongo D, Tang X, Zhang X, Engleman EG, Strober S. Tolerogenic interactions between CD8(+) dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. Blood. 2017;129(12):1718–28.28096089 10.1182/blood-2016-07-723015
174. Castegna A Gissi R Menga A Montopoli M Favia M Viola A Canton M Pharmacological targets of metabolism in disease: opportunities from macrophages Pharmacol Ther 2020 210 107521 10.1016/j.pharmthera.2020.107521 32151665
Castegna A, Gissi R, Menga A, Montopoli M, Favia M, Viola A, Canton M. Pharmacological targets of metabolism in disease: opportunities from macrophages. Pharmacol Ther. 2020;210: 107521.32151665 10.1016/j.pharmthera.2020.107521
175. Lee WL Liu CH Cheng M Chang WH Liu WM Wang PH Focus on the primary prevention of intrauterine adhesions: current concept and vision Int J Mol Sci 2021 22 10 5175 10.3390/ijms22105175 34068335
Lee WL, Liu CH, Cheng M, Chang WH, Liu WM, Wang PH. Focus on the primary prevention of intrauterine adhesions: current concept and vision. Int J Mol Sci. 2021;22(10):5175.34068335 10.3390/ijms22105175
176. Wang Y Pang J Wang Q Yan L Wang L Xing Z Wang C Zhang J Dong L Delivering antisense oligonucleotides across the blood-brain barrier by tumor cell-derived small apoptotic bodies Adv Sci 2021 8 13 2004929 10.1002/advs.202004929
Wang Y, Pang J, Wang Q, Yan L, Wang L, Xing Z, Wang C, Zhang J, Dong L. Delivering antisense oligonucleotides across the blood-brain barrier by tumor cell-derived small apoptotic bodies. Adv Sci. 2021;8(13):2004929.10.1002/advs.202004929
177. Singh Patel P Srivastava R Panchawat S Role of apoptotic-targeted phytoconstitutent-loaded antipsoriatic Recent Pat Nanotechnol 2023 10.2174/1872210517666230201103935
Singh Patel P, Srivastava R, Panchawat S. Role of apoptotic-targeted phytoconstitutent-loaded antipsoriatic. Recent Pat Nanotechnol. 2023. 10.2174/1872210517666230201103935.10.2174/1872210517666230201103935
178. Mao W Wang K Zhang W Chen S Xie J Zheng Z Li X Zhang N Zhang Y Zhang H Peng B Yao X Che J Zheng J Chen M Li W Transfection with plasmid-encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal cell carcinoma J Exp Clin Cancer Res 2022 41 1 252 10.1186/s13046-022-02467-2 35986402
Mao W, Wang K, Zhang W, Chen S, Xie J, Zheng Z, Li X, Zhang N, Zhang Y, Zhang H, Peng B, Yao X, Che J, Zheng J, Chen M, Li W. Transfection with plasmid-encoding lncRNA-SLERCC nanoparticle-mediated delivery suppressed tumor progression in renal cell carcinoma. J Exp Clin Cancer Res. 2022;41(1):252.35986402 10.1186/s13046-022-02467-2
179. Sasaki S Amara RR Oran AE Smith JM Robinson HL Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases Nat Biotechnol 2001 19 6 543 547 10.1038/89289 11385458
Sasaki S, Amara RR, Oran AE, Smith JM, Robinson HL. Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases. Nat Biotechnol. 2001;19(6):543–7.11385458 10.1038/89289
180. Zhao D Tao W Li S Chen Y Sun Y He Z Sun B Sun J Apoptotic body–mediated intercellular delivery for enhanced drug penetration and whole tumor destruction Sci Adv 2021 10.1126/sciadv.abg0880 34936449
Zhao D, Tao W, Li S, Chen Y, Sun Y, He Z, Sun B, Sun J. Apoptotic body–mediated intercellular delivery for enhanced drug penetration and whole tumor destruction. Sci Adv. 2021. 10.1126/sciadv.abg0880.34936449 10.1126/sciadv.abg0880
181. Zheng L Hu X Wu H Mo L Xie S Li J Peng C Xu S Qiu L Tan W In Vivo monocyte/macrophage-hitchhiked intratumoral accumulation of nanomedicines for enhanced tumor therapy J Am Chem Soc 2020 142 1 382 391 10.1021/jacs.9b11046 31801020
Zheng L, Hu X, Wu H, Mo L, Xie S, Li J, Peng C, Xu S, Qiu L, Tan W. In Vivo monocyte/macrophage-hitchhiked intratumoral accumulation of nanomedicines for enhanced tumor therapy. J Am Chem Soc. 2020;142(1):382–91.31801020 10.1021/jacs.9b11046
182. Wei X Zhang L Yang Y Hou Y Xu Y Wang Z Su H Han F Han J Liu P Hu S Koci MD Sun X Zhang C LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity Cell Rep 2022 39 9 110880 10.1016/j.celrep.2022.110880 35649354
Wei X, Zhang L, Yang Y, Hou Y, Xu Y, Wang Z, Su H, Han F, Han J, Liu P, Hu S, Koci MD, Sun X, Zhang C. LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity. Cell Rep. 2022;39(9): 110880.35649354 10.1016/j.celrep.2022.110880
183. Carozza JA Böhnert V Nguyen KC Skariah G Shaw KE Brown JA Rafat M von Eyben R Graves EE Glenn JS Smith M Li L Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity Nature cancer 2020 1 2 184 196 10.1038/s43018-020-0028-4 33768207
Carozza JA, Böhnert V, Nguyen KC, Skariah G, Shaw KE, Brown JA, Rafat M, von Eyben R, Graves EE, Glenn JS, Smith M, Li L. Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nature cancer. 2020;1(2):184–96.33768207 10.1038/s43018-020-0028-4
184. Zhou C Chen X Planells-Cases R Chu J Wang L Cao L Li Z López-Cayuqueo KI Xie Y Ye S Wang X Ullrich F Ma S Fang Y Zhang X Qian Z Liang X Cai SQ Jiang Z Zhou D Leng Q Xiao TS Lan K Yang J Li H Peng C Qiu Z Jentsch TJ Xiao H Transfer of cGAMP into bystander cells via lrrc8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity Immunity 2020 52 5 767 781.e6 10.1016/j.immuni.2020.03.016 32277911
Zhou C, Chen X, Planells-Cases R, Chu J, Wang L, Cao L, Li Z, López-Cayuqueo KI, Xie Y, Ye S, Wang X, Ullrich F, Ma S, Fang Y, Zhang X, Qian Z, Liang X, Cai SQ, Jiang Z, Zhou D, Leng Q, Xiao TS, Lan K, Yang J, Li H, Peng C, Qiu Z, Jentsch TJ, Xiao H. Transfer of cGAMP into bystander cells via lrrc8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity. Immunity. 2020;52(5):767-781.e6.32277911 10.1016/j.immuni.2020.03.016
185. Bao P Zheng ZT Ye JJ Zhang XZ Apoptotic body-mediated intracellular delivery strategy for enhanced sting activation and improved tumor immunogenicity Nano Lett 2022 22 6 2217 2227 10.1021/acs.nanolett.1c03996 35254071
Bao P, Zheng ZT, Ye JJ, Zhang XZ. Apoptotic body-mediated intracellular delivery strategy for enhanced sting activation and improved tumor immunogenicity. Nano Lett. 2022;22(6):2217–27.35254071 10.1021/acs.nanolett.1c03996
186. Perez GI Bernard MP Vocelle D Zarea AA Saleh NA Gagea MA Schneider D Bauzon M Hermiston T Kanada M Phosphatidylserine-exposing annexin A1-positive extracellular vesicles: potential cancer biomarkers Vaccines 2023 11 3 639 10.3390/vaccines11030639 36992223
Perez GI, Bernard MP, Vocelle D, Zarea AA, Saleh NA, Gagea MA, Schneider D, Bauzon M, Hermiston T, Kanada M. Phosphatidylserine-exposing annexin A1-positive extracellular vesicles: potential cancer biomarkers. Vaccines. 2023;11(3):639.36992223 10.3390/vaccines11030639
187. Ginckels P Holvoet P Oxidative stress and inflammation in cardiovascular diseases and cancer: role of non-coding RNAs Yale J Biol Med 2022 95 1 129 152 35370493
Ginckels P, Holvoet P. Oxidative stress and inflammation in cardiovascular diseases and cancer: role of non-coding RNAs. Yale J Biol Med. 2022;95(1):129–52.35370493
188. Zia A Farkhondeh T Pourbagher-Shahri AM Samarghandian S The role of curcumin in aging and senescence: molecular mechanisms Biomed Pharmacother 2021 134 111119 10.1016/j.biopha.2020.111119 33360051
Zia A, Farkhondeh T, Pourbagher-Shahri AM, Samarghandian S. The role of curcumin in aging and senescence: molecular mechanisms. Biomed Pharmacother. 2021;134: 111119.33360051 10.1016/j.biopha.2020.111119
189. Ji H Zhang C Xu F Mao Q Xia R Chen M Wang W Lv S Li W Shi X Inhaled pro-efferocytic nanozymes promote resolution of acute lung injury Adv Sci 2022 10.1002/advs.202201696
Ji H, Zhang C, Xu F, Mao Q, Xia R, Chen M, Wang W, Lv S, Li W, Shi X. Inhaled pro-efferocytic nanozymes promote resolution of acute lung injury. Adv Sci. 2022. 10.1002/advs.202201696.10.1002/advs.202201696
190. Royo F Cossío U Ruiz de Angulo A Llop J Falcon-Perez JM Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice Nanoscale 2019 11 4 1531 1537 10.1039/C8NR03900C 30623961
Royo F, Cossío U, Ruiz de Angulo A, Llop J, Falcon-Perez JM. Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice. Nanoscale. 2019;11(4):1531–7.30623961 10.1039/C8NR03900C
191. Johnson V Vasu S Kumar US Kumar M Surface-engineered extracellular vesicles in cancer immunotherapy Cancers 2023 15 10 2838 10.3390/cancers15102838 37345176
Johnson V, Vasu S, Kumar US, Kumar M. Surface-engineered extracellular vesicles in cancer immunotherapy. Cancers. 2023;15(10):2838.37345176 10.3390/cancers15102838
192. Tao SC Li XR Wei WJ Wei ZY Zhang CR Wang F Dawes H Guo SC Polymeric coating on β-TCP scaffolds provides immobilization of small extracellular vesicles with surface-functionalization and ZEB1-Loading for bone defect repair in diabetes mellitus Biomaterials 2022 283 121465 10.1016/j.biomaterials.2022.121465 35286850
Tao SC, Li XR, Wei WJ, Wei ZY, Zhang CR, Wang F, Dawes H, Guo SC. Polymeric coating on β-TCP scaffolds provides immobilization of small extracellular vesicles with surface-functionalization and ZEB1-Loading for bone defect repair in diabetes mellitus. Biomaterials. 2022;283: 121465.35286850 10.1016/j.biomaterials.2022.121465
193. Pham TC Jayasinghe MK Pham TT Yang Y Wei L Usman WM Chen H Pirisinu M Gong J Kim S Peng B Wang W Chan C Ma V Nguyen NTH Kappei D Nguyen XH Cho WC Shi J Le MTN Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery J Extracell Vesicles 2021 10 4 e12057 10.1002/jev2.12057 33643546
Pham TC, Jayasinghe MK, Pham TT, Yang Y, Wei L, Usman WM, Chen H, Pirisinu M, Gong J, Kim S, Peng B, Wang W, Chan C, Ma V, Nguyen NTH, Kappei D, Nguyen XH, Cho WC, Shi J, Le MTN. Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery. J Extracell Vesicles. 2021;10(4): e12057.33643546 10.1002/jev2.12057
194. Wei Z Chen Z Zhao Y Fan F Xiong W Song S Yin Y Hu J Yang K Yang L Xu B Ge J Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment Biomaterials 2021 275 121000 10.1016/j.biomaterials.2021.121000 34218049
Wei Z, Chen Z, Zhao Y, Fan F, Xiong W, Song S, Yin Y, Hu J, Yang K, Yang L, Xu B, Ge J. Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment. Biomaterials. 2021;275: 121000.34218049 10.1016/j.biomaterials.2021.121000
195. Yuan Z Kolluri KK Gowers KH Janes SM TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy J Extracell Vesicles 2017 6 1 1265291 10.1080/20013078.2017.1265291 28326166
Yuan Z, Kolluri KK, Gowers KH, Janes SM. TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. J Extracell Vesicles. 2017;6(1):1265291.28326166 10.1080/20013078.2017.1265291
196. Ohno S Takanashi M Sudo K Ueda S Ishikawa A Matsuyama N Fujita K Mizutani T Ohgi T Ochiya T Gotoh N Kuroda M Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells Mol Ther 2013 21 1 185 191 10.1038/mt.2012.180 23032975
Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21(1):185–91.23032975 10.1038/mt.2012.180
197. Zou X Yuan M Zhang T Wei H Xu S Jiang N Zheng N Wu Z Extracellular vesicles expressing a single-chain variable fragment of an HIV-1 specific antibody selectively target Env(+) tissues Theranostics 2019 9 19 5657 5671 10.7150/thno.33925 31534509
Zou X, Yuan M, Zhang T, Wei H, Xu S, Jiang N, Zheng N, Wu Z. Extracellular vesicles expressing a single-chain variable fragment of an HIV-1 specific antibody selectively target Env(+) tissues. Theranostics. 2019;9(19):5657–71.31534509 10.7150/thno.33925
198. Urabe F Kosaka N Ito K Kimura T Egawa S Ochiya T Extracellular vesicles as biomarkers and therapeutic targets for cancer Am J Physiol Cell Physiol 2020 318 1 C29 c39 10.1152/ajpcell.00280.2019 31693397
Urabe F, Kosaka N, Ito K, Kimura T, Egawa S, Ochiya T. Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am J Physiol Cell Physiol. 2020;318(1):C29-c39.31693397 10.1152/ajpcell.00280.2019
199. Stickney Z Losacco J McDevitt S Zhang Z Lu B Development of exosome surface display technology in living human cells Biochem Biophys Res Commun 2016 472 1 53 59 10.1016/j.bbrc.2016.02.058 26902116
Stickney Z, Losacco J, McDevitt S, Zhang Z, Lu B. Development of exosome surface display technology in living human cells. Biochem Biophys Res Commun. 2016;472(1):53–9.26902116 10.1016/j.bbrc.2016.02.058
200. Takahashi Y Nishikawa M Shinotsuka H Matsui Y Ohara S Imai T Takakura Y Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection J Biotechnol 2013 165 2 77 84 10.1016/j.jbiotec.2013.03.013 23562828
Takahashi Y, Nishikawa M, Shinotsuka H, Matsui Y, Ohara S, Imai T, Takakura Y. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol. 2013;165(2):77–84.23562828 10.1016/j.jbiotec.2013.03.013
201. Wang M Altinoglu S Takeda YS Xu Q Integrating protein engineering and bioorthogonal click conjugation for extracellular vesicle modulation and intracellular delivery PLoS ONE 2015 10 11 e0141860 10.1371/journal.pone.0141860 26529317
Wang M, Altinoglu S, Takeda YS, Xu Q. Integrating protein engineering and bioorthogonal click conjugation for extracellular vesicle modulation and intracellular delivery. PLoS ONE. 2015;10(11): e0141860.26529317 10.1371/journal.pone.0141860
202. Vella LJ Hill AF Cheng L Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer's and parkinson's disease Int J Mol Sci 2016 17 2 173 10.3390/ijms17020173 26861304
Vella LJ, Hill AF, Cheng L. Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and parkinson’s disease. Int J Mol Sci. 2016;17(2):173.26861304 10.3390/ijms17020173
203. Armstrong JP Holme MN Stevens MM Re-engineering extracellular vesicles as smart nanoscale therapeutics ACS Nano 2017 11 1 69 83 10.1021/acsnano.6b07607 28068069
Armstrong JP, Holme MN, Stevens MM. Re-engineering extracellular vesicles as smart nanoscale therapeutics. ACS Nano. 2017;11(1):69–83.28068069 10.1021/acsnano.6b07607
204. Lee TS Kim Y Zhang W Song IH Tung CH (2018) Facile metabolic glycan labeling strategy for exosome tracking Biochim Biophys Acta Gen Subj 1862 5 1091 1100
Lee TS, Kim Y, Zhang W, Song IH, Tung CH. (2018) Facile metabolic glycan labeling strategy for exosome tracking. Biochim Biophys Acta Gen Subj. 1862;5:1091–100.
205. Lee J Lee H Goh U Kim J Jeong M Lee J Park JH Cellular engineering with membrane fusogenic liposomes to produce functionalized extracellular vesicles ACS Appl Mater Interfaces 2016 8 11 6790 6795 10.1021/acsami.6b01315 26954538
Lee J, Lee H, Goh U, Kim J, Jeong M, Lee J, Park JH. Cellular engineering with membrane fusogenic liposomes to produce functionalized extracellular vesicles. ACS Appl Mater Interfaces. 2016;8(11):6790–5.26954538 10.1021/acsami.6b01315
206. Guo SC Tao SC Dawn H Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles J Extracell Vesicles 2018 7 1 1508271 10.1080/20013078.2018.1508271 30151077
Guo SC, Tao SC, Dawn H. Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles. J Extracell Vesicles. 2018;7(1):1508271.30151077 10.1080/20013078.2018.1508271
207. Pomatto MAC Negro F Camussi G Optimized protocol for plasma-derived extracellular vesicles loading with synthetic mirna mimic using electroporation Methods Mol Biol 2022 2504 219 230 10.1007/978-1-0716-2341-1_16 35467290
Pomatto MAC, Negro F, Camussi G. Optimized protocol for plasma-derived extracellular vesicles loading with synthetic mirna mimic using electroporation. Methods Mol Biol. 2022;2504:219–30.35467290 10.1007/978-1-0716-2341-1_16
208. Akagi T Kato K Kobayashi M Kosaka N Ochiya T Ichiki T On-chip immunoelectrophoresis of extracellular vesicles released from human breast cancer cells PLoS ONE 2015 10 4 e0123603 10.1371/journal.pone.0123603 25928805
Akagi T, Kato K, Kobayashi M, Kosaka N, Ochiya T, Ichiki T. On-chip immunoelectrophoresis of extracellular vesicles released from human breast cancer cells. PLoS ONE. 2015;10(4): e0123603.25928805 10.1371/journal.pone.0123603
209. Románszki L Varga Z Mihály J Keresztes Z Thompson M Electromagnetic piezoelectric acoustic sensor detection of extracellular vesicles through interaction with detached vesicle proteins Biosensors 2020 10 11 173 10.3390/bios10110173 33187356
Románszki L, Varga Z, Mihály J, Keresztes Z, Thompson M. Electromagnetic piezoelectric acoustic sensor detection of extracellular vesicles through interaction with detached vesicle proteins. Biosensors. 2020;10(11):173.33187356 10.3390/bios10110173
210. Rayamajhi S Aryal S Surface functionalization strategies of extracellular vesicles J Mater Chem B 2020 8 21 4552 4569 10.1039/D0TB00744G 32377649
Rayamajhi S, Aryal S. Surface functionalization strategies of extracellular vesicles. J Mater Chem B. 2020;8(21):4552–69.32377649 10.1039/D0TB00744G
211. Cheng H Fan JH Zhao LP Fan GL Zheng RR Qiu XZ Yu XY Li SY Zhang XZ Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy Biomaterials 2019 211 14 24 10.1016/j.biomaterials.2019.05.004 31078049
Cheng H, Fan JH, Zhao LP, Fan GL, Zheng RR, Qiu XZ, Yu XY, Li SY, Zhang XZ. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials. 2019;211:14–24.31078049 10.1016/j.biomaterials.2019.05.004
212. Fröjd MJ Flärdh K Extrusion of extracellular membrane vesicles from hyphal tips of Streptomyces venezuelae coupled to cell-wall stress Microbiology 2019 165 12 1295 1305 10.1099/mic.0.000836 31282851
Fröjd MJ, Flärdh K. Extrusion of extracellular membrane vesicles from hyphal tips of Streptomyces venezuelae coupled to cell-wall stress. Microbiology. 2019;165(12):1295–305.31282851 10.1099/mic.0.000836
213. Van Deun J Roux Q Deville S Van Acker T Rappu P Miinalainen I Heino J Vanhaecke F De Geest BG De Wever O Hendrix A Feasibility of mechanical extrusion to coat nanoparticles with extracellular vesicle membranes Cells 2020 9 8 1797 10.3390/cells9081797 32751082
Van Deun J, Roux Q, Deville S, Van Acker T, Rappu P, Miinalainen I, Heino J, Vanhaecke F, De Geest BG, De Wever O, Hendrix A. Feasibility of mechanical extrusion to coat nanoparticles with extracellular vesicle membranes. Cells. 2020;9(8):1797.32751082 10.3390/cells9081797
214. Bose RJC Uday Kumar S Zeng Y Afjei R Robinson E Lau K Bermudez A Habte F Pitteri SJ Sinclair R Willmann JK Massoud TF Gambhir SS Paulmurugan R Tumor cell-derived extracellular vesicle-coated nanocarriers: an efficient theranostic platform for the cancer-specific delivery of anti-miR-21 and imaging agents ACS Nano 2018 12 11 10817 10832 10.1021/acsnano.8b02587 30346694
Bose RJC, Uday Kumar S, Zeng Y, Afjei R, Robinson E, Lau K, Bermudez A, Habte F, Pitteri SJ, Sinclair R, Willmann JK, Massoud TF, Gambhir SS, Paulmurugan R. Tumor cell-derived extracellular vesicle-coated nanocarriers: an efficient theranostic platform for the cancer-specific delivery of anti-miR-21 and imaging agents. ACS Nano. 2018;12(11):10817–32.30346694 10.1021/acsnano.8b02587
215. Bose RJ Kumar US Garcia-Marques F Zeng Y Habte F McCarthy JR Pitteri S Massoud TF Paulmurugan R Engineered cell-derived vesicles displaying targeting peptide and functionalized with nanocarriers for therapeutic microrna delivery to triple-negative breast cancer in mice Adv Healthc Mater 2022 11 5 e2101387 10.1002/adhm.202101387 34879180
Bose RJ, Kumar US, Garcia-Marques F, Zeng Y, Habte F, McCarthy JR, Pitteri S, Massoud TF, Paulmurugan R. Engineered cell-derived vesicles displaying targeting peptide and functionalized with nanocarriers for therapeutic microrna delivery to triple-negative breast cancer in mice. Adv Healthc Mater. 2022;11(5): e2101387.34879180 10.1002/adhm.202101387
216. Kooijmans SAA Gitz-Francois J Schiffelers RM Vader P Recombinant phosphatidylserine-binding nanobodies for targeting of extracellular vesicles to tumor cells: a plug-and-play approach Nanoscale 2018 10 5 2413 2426 10.1039/C7NR06966A 29334397
Kooijmans SAA, Gitz-Francois J, Schiffelers RM, Vader P. Recombinant phosphatidylserine-binding nanobodies for targeting of extracellular vesicles to tumor cells: a plug-and-play approach. Nanoscale. 2018;10(5):2413–26.29334397 10.1039/C7NR06966A
217. Jia G Han Y An Y Ding Y He C Wang X Tang Q NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo Biomaterials 2018 178 302 316 10.1016/j.biomaterials.2018.06.029 29982104
Jia G, Han Y, An Y, Ding Y, He C, Wang X, Tang Q. NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials. 2018;178:302–16.29982104 10.1016/j.biomaterials.2018.06.029
218. Hosseini NF Amini R Ramezani M Saidijam M Hashemi SM Najafi R AS1411 aptamer-functionalized exosomes in the targeted delivery of doxorubicin in fighting colorectal cancer Biomed Pharmacother 2022 155 113690 10.1016/j.biopha.2022.113690 36099793
Hosseini NF, Amini R, Ramezani M, Saidijam M, Hashemi SM, Najafi R. AS1411 aptamer-functionalized exosomes in the targeted delivery of doxorubicin in fighting colorectal cancer. Biomed Pharmacother. 2022;155: 113690.36099793 10.1016/j.biopha.2022.113690
219. Wang J Wang M Jiang N Ding S Peng Q Zheng L Emerging chemical engineering of exosomes as "bioscaffolds" in diagnostics and therapeutics Genes Dis 2023 10 4 1494 1512 10.1016/j.gendis.2022.10.020 37397530
Wang J, Wang M, Jiang N, Ding S, Peng Q, Zheng L. Emerging chemical engineering of exosomes as “bioscaffolds” in diagnostics and therapeutics. Genes Dis. 2023;10(4):1494–512.37397530 10.1016/j.gendis.2022.10.020
220. Mizuta R Sasaki Y Kawasaki R Katagiri K Sawada SI Mukai SA Akiyoshi K Magnetically navigated intracellular delivery of extracellular vesicles using amphiphilic nanogels Bioconjug Chem 2019 30 8 2150 2155 10.1021/acs.bioconjchem.9b00369 31322343
Mizuta R, Sasaki Y, Kawasaki R, Katagiri K, Sawada SI, Mukai SA, Akiyoshi K. Magnetically navigated intracellular delivery of extracellular vesicles using amphiphilic nanogels. Bioconjug Chem. 2019;30(8):2150–5.31322343 10.1021/acs.bioconjchem.9b00369
221. Wang J Li W Zhang L Ban L Chen P Du W Feng X Liu BF Chemically edited exosomes with dual ligand purified by microfluidic device for active targeted drug delivery to tumor cells ACS Appl Mater Interfaces 2017 9 33 27441 27452 10.1021/acsami.7b06464 28762264
Wang J, Li W, Zhang L, Ban L, Chen P, Du W, Feng X, Liu BF. Chemically edited exosomes with dual ligand purified by microfluidic device for active targeted drug delivery to tumor cells. ACS Appl Mater Interfaces. 2017;9(33):27441–52.28762264 10.1021/acsami.7b06464
222. Qi H Liu C Long L Ren Y Zhang S Chang X Qian X Jia H Zhao J Sun J Hou X Yuan X Kang C Blood exosomes endowed with magnetic and targeting properties for cancer therapy ACS Nano 2016 10 3 3323 3333 10.1021/acsnano.5b06939 26938862
Qi H, Liu C, Long L, Ren Y, Zhang S, Chang X, Qian X, Jia H, Zhao J, Sun J, Hou X, Yuan X, Kang C. Blood exosomes endowed with magnetic and targeting properties for cancer therapy. ACS Nano. 2016;10(3):3323–33.26938862 10.1021/acsnano.5b06939
223. Smyth T Petrova K Payton NM Persaud I Redzic JS Graner MW Smith-Jones P Anchordoquy TJ Surface functionalization of exosomes using click chemistry Bioconjug Chem 2014 25 10 1777 1784 10.1021/bc500291r 25220352
Smyth T, Petrova K, Payton NM, Persaud I, Redzic JS, Graner MW, Smith-Jones P, Anchordoquy TJ. Surface functionalization of exosomes using click chemistry. Bioconjug Chem. 2014;25(10):1777–84.25220352 10.1021/bc500291r
224. Zhang M Vojtech L Ye Z Hladik F Nance E Quantum dot labeling and visualization of extracellular vesicles ACS Appl Nano Mater 2020 3 7 7211 7222 10.1021/acsanm.0c01553 34568770
Zhang M, Vojtech L, Ye Z, Hladik F, Nance E. Quantum dot labeling and visualization of extracellular vesicles. ACS Appl Nano Mater. 2020;3(7):7211–22.34568770 10.1021/acsanm.0c01553
225. Salunkhe S Dheeraj M Basak D Chitkara A Mittal, surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: strategies and significance J Control Release 2020 326 599 614 10.1016/j.jconrel.2020.07.042 32730952
Salunkhe S, Dheeraj M, Basak D, Chitkara A. Mittal, surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: strategies and significance. J Control Release. 2020;326:599–614.32730952 10.1016/j.jconrel.2020.07.042
226. Guo ZY Tang Y Cheng YC Exosomes as targeted delivery drug system: advances in exosome loading, surface functionalization and potential for clinical application Curr Drug Deliv 2022 10.2174/1567201819666220613150814 34126896
Guo ZY, Tang Y, Cheng YC. Exosomes as targeted delivery drug system: advances in exosome loading, surface functionalization and potential for clinical application. Curr Drug Deliv. 2022. 10.2174/1567201819666220613150814.34126896 10.2174/1567201819666220613150814
227. Yi L Wang B Feng Q Yan Y Ding CF Mao H Surface functionalization modification of ultra-hydrophilic magnetic spheres with mesoporous silica for specific identification of glycopeptides in serum exosomes Anal Bioanal Chem 2023 415 9 1741 1749 10.1007/s00216-023-04575-0 36790462
Yi L, Wang B, Feng Q, Yan Y, Ding CF, Mao H. Surface functionalization modification of ultra-hydrophilic magnetic spheres with mesoporous silica for specific identification of glycopeptides in serum exosomes. Anal Bioanal Chem. 2023;415(9):1741–9.36790462 10.1007/s00216-023-04575-0
228. Lu J Wang M Han Y Deng Y Zeng Y Li C Yang J Li G Functionalization of covalent organic frameworks with dna via covalent modification and the application to exosomes detection Anal Chem 2022 94 12 5055 5061 10.1021/acs.analchem.1c05222 35290034
Lu J, Wang M, Han Y, Deng Y, Zeng Y, Li C, Yang J, Li G. Functionalization of covalent organic frameworks with dna via covalent modification and the application to exosomes detection. Anal Chem. 2022;94(12):5055–61.35290034 10.1021/acs.analchem.1c05222
229. Gaurav I Thakur A Iyaswamy A Wang X Chen X Yang Z Factors affecting extracellular vesicles based drug delivery systems Molecules 2021 26 6 1544 10.3390/molecules26061544 33799765
Gaurav I, Thakur A, Iyaswamy A, Wang X, Chen X, Yang Z. Factors affecting extracellular vesicles based drug delivery systems. Molecules. 2021;26(6):1544.33799765 10.3390/molecules26061544
230. Woo J Ko KW Cha SG Heo Y Han DK Comparison of surface functionalization of plga composite to immobilize extracellular vesicles Polymers 2021 13 21 3643 10.3390/polym13213643 34771200
Woo J, Ko KW, Cha SG, Heo Y, Han DK. Comparison of surface functionalization of plga composite to immobilize extracellular vesicles. Polymers. 2021;13(21):3643.34771200 10.3390/polym13213643
231. Zaruba M Roschitz L Sami H Ogris M Gerner W Metzner C Surface modification of E. coli outer membrane vesicles with glycosylphosphatidylinositol-anchored proteins: generating pro/eukaryote chimera constructs Membranes 2021 11 6 428 10.3390/membranes11060428 34199851
Zaruba M, Roschitz L, Sami H, Ogris M, Gerner W, Metzner C. Surface modification of E. coli outer membrane vesicles with glycosylphosphatidylinositol-anchored proteins: generating pro/eukaryote chimera constructs. Membranes. 2021;11(6):428.34199851 10.3390/membranes11060428
232. Wu L Kim Y Seon GM Choi SH Park HC Son G Kim SM Lim BS Yang HC Effects of RGD-grafted phosphatidylserine-containing liposomes on the polarization of macrophages and bone tissue regeneration Biomaterials 2021 279 121239 10.1016/j.biomaterials.2021.121239 34753037
Wu L, Kim Y, Seon GM, Choi SH, Park HC, Son G, Kim SM, Lim BS, Yang HC. Effects of RGD-grafted phosphatidylserine-containing liposomes on the polarization of macrophages and bone tissue regeneration. Biomaterials. 2021;279: 121239.34753037 10.1016/j.biomaterials.2021.121239
233. Kraynak CA Huang W Bender EC Wang JL Hanafy MS Cui Z Suggs LJ Apoptotic body-inspired nanoparticles target macrophages at sites of inflammation to support an anti-inflammatory phenotype shift Int J Pharm 2022 618 121634 10.1016/j.ijpharm.2022.121634 35247497
Kraynak CA, Huang W, Bender EC, Wang JL, Hanafy MS, Cui Z, Suggs LJ. Apoptotic body-inspired nanoparticles target macrophages at sites of inflammation to support an anti-inflammatory phenotype shift. Int J Pharm. 2022;618: 121634.35247497 10.1016/j.ijpharm.2022.121634
234. Kraynak CA Yan DJ Suggs LJ Modulating inflammatory macrophages with an apoptotic body-inspired nanoparticle Acta Biomater 2020 108 250 260 10.1016/j.actbio.2020.03.041 32251779
Kraynak CA, Yan DJ, Suggs LJ. Modulating inflammatory macrophages with an apoptotic body-inspired nanoparticle. Acta Biomater. 2020;108:250–60.32251779 10.1016/j.actbio.2020.03.041
235. Zhang G Xue H Sun D Yang S Tu M Zeng R Soft apoptotic-cell-inspired nanoparticles persistently bind to macrophage membranes and promote anti-inflammatory and pro-healing effects Acta Biomater 2021 131 452 463 10.1016/j.actbio.2021.07.002 34245890
Zhang G, Xue H, Sun D, Yang S, Tu M, Zeng R. Soft apoptotic-cell-inspired nanoparticles persistently bind to macrophage membranes and promote anti-inflammatory and pro-healing effects. Acta Biomater. 2021;131:452–63.34245890 10.1016/j.actbio.2021.07.002
236. Sun D Zhang G Xie M Wang Y Liang X Tu M Su Z Zeng R Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury J Nanobiotechnology 2023 21 1 172 10.1186/s12951-023-01930-2 37248505
Sun D, Zhang G, Xie M, Wang Y, Liang X, Tu M, Su Z, Zeng R. Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury. J Nanobiotechnology. 2023;21(1):172.37248505 10.1186/s12951-023-01930-2
237. Lai Y Xu X Zhu Z Hua Z Highly efficient siRNA transfection in macrophages using apoptotic body-mimic Ca-PS lipopolyplex Int J Nanomedicine 2018 13 6603 6623 10.2147/IJN.S176991 30425477
Lai Y, Xu X, Zhu Z, Hua Z. Highly efficient siRNA transfection in macrophages using apoptotic body-mimic Ca-PS lipopolyplex. Int J Nanomedicine. 2018;13:6603–23.30425477 10.2147/IJN.S176991
238. Wu L Seon GM Kim Y Choi SH Vo QC Yang HC Enhancing effect of sodium butyrate on phosphatidylserine-liposome-induced macrophage polarization Inflamm Res 2022 71 5–6 641 652 10.1007/s00011-022-01563-5 35347345
Wu L, Seon GM, Kim Y, Choi SH, Vo QC, Yang HC. Enhancing effect of sodium butyrate on phosphatidylserine-liposome-induced macrophage polarization. Inflamm Res. 2022;71(5–6):641–52.35347345 10.1007/s00011-022-01563-5
239. Toita R Kang JH Tsuchiya A Phosphatidylserine liposome multilayers mediate the M1-to-M2 macrophage polarization to enhance bone tissue regeneration Acta Biomater 2022 154 583 596 10.1016/j.actbio.2022.10.024 36273800
Toita R, Kang JH, Tsuchiya A. Phosphatidylserine liposome multilayers mediate the M1-to-M2 macrophage polarization to enhance bone tissue regeneration. Acta Biomater. 2022;154:583–96.36273800 10.1016/j.actbio.2022.10.024
240. Quan H Park HC Kim Y Yang HC Modulation of the anti-inflammatory effects of phosphatidylserine-containing liposomes by PEGylation J Biomed Mater Res A 2017 105 5 1479 1486 10.1002/jbm.a.35981 27998010
Quan H, Park HC, Kim Y, Yang HC. Modulation of the anti-inflammatory effects of phosphatidylserine-containing liposomes by PEGylation. J Biomed Mater Res A. 2017;105(5):1479–86.27998010 10.1002/jbm.a.35981
241. Saffari PM Alijanpour S Takzaree N Sahebgharani M Etemad-Moghadam S Noorbakhsh F Partoazar A Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer's disease model Life Sci 2020 255 117861 10.1016/j.lfs.2020.117861 32473247
Saffari PM, Alijanpour S, Takzaree N, Sahebgharani M, Etemad-Moghadam S, Noorbakhsh F, Partoazar A. Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer’s disease model. Life Sci. 2020;255: 117861.32473247 10.1016/j.lfs.2020.117861
242. Eskandarynasab M Doustimotlagh AH Takzaree N Etemad-Moghadam S Alaeddini M Dehpour AR Goudarzi R Partoazar A Phosphatidylserine nanoliposomes inhibit glucocorticoid-induced osteoporosis: a potential combination therapy with alendronate Life Sci 2020 257 118033 10.1016/j.lfs.2020.118033 32621924
Eskandarynasab M, Doustimotlagh AH, Takzaree N, Etemad-Moghadam S, Alaeddini M, Dehpour AR, Goudarzi R, Partoazar A. Phosphatidylserine nanoliposomes inhibit glucocorticoid-induced osteoporosis: a potential combination therapy with alendronate. Life Sci. 2020;257: 118033.32621924 10.1016/j.lfs.2020.118033
243. Poerio N Caccamo NR La Manna MP Olimpieri T De Angelis LH D'Andrea MM Dieli F Fraziano M Phosphatidylserine liposomes reduce inflammatory response, mycobacterial viability, and hiv replication in coinfected human macrophages J Infect Dis 2022 225 9 1675 1679 10.1093/infdis/jiab602 34910807
Poerio N, Caccamo NR, La Manna MP, Olimpieri T, De Angelis LH, D’Andrea MM, Dieli F, Fraziano M. Phosphatidylserine liposomes reduce inflammatory response, mycobacterial viability, and hiv replication in coinfected human macrophages. J Infect Dis. 2022;225(9):1675–9.34910807 10.1093/infdis/jiab602
244. Nakagawa Y Saitou A Aoyagi T Naito M Ebara M Apoptotic cell membrane-inspired polymer for immunosuppression ACS Macro Lett 2017 6 9 1020 1024 10.1021/acsmacrolett.7b00592 35650882
Nakagawa Y, Saitou A, Aoyagi T, Naito M, Ebara M. Apoptotic cell membrane-inspired polymer for immunosuppression. ACS Macro Lett. 2017;6(9):1020–4.35650882 10.1021/acsmacrolett.7b00592
245. Gangadaran P Ahn BC Extracellular vesicle- and extracellular vesicle mimetics-based drug delivery systems: new perspectives, challenges, and clinical developments Pharmaceutics 2020 12 5 442 10.3390/pharmaceutics12050442 32403320
Gangadaran P, Ahn BC. Extracellular vesicle- and extracellular vesicle mimetics-based drug delivery systems: new perspectives, challenges, and clinical developments. Pharmaceutics. 2020;12(5):442.32403320 10.3390/pharmaceutics12050442
