
==== Front
Nat Commun
Nat Commun
Nature Communications
2041-1723
Nature Publishing Group UK London

39289401
52416
10.1038/s41467-024-52416-0
Review Article
Transvascular transport of nanocarriers for tumor delivery
http://orcid.org/0000-0002-7837-7874
Li Xin 123
http://orcid.org/0000-0003-1425-6093
Hu Yong 3
http://orcid.org/0000-0001-7114-1095
Zhang Xingcai xingcai@stanford.edu

4
http://orcid.org/0000-0001-6785-6645
Shi Xiangyang 5
http://orcid.org/0000-0003-1672-6650
Parak Wolfgang J. wolfgang.parak@uni-hamburg.de

6
http://orcid.org/0000-0003-1825-7798
Pich Andrij pich@dwi.rwth-aachen.de

127
1 https://ror.org/0186h8060 grid.452391.8 0000 0000 9737 4092 DWI-Leibniz-Institute for Interactive Materials, Aachen, 52056 Germany
2 https://ror.org/04xfq0f34 grid.1957.a 0000 0001 0728 696X Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen, 52074 Germany
3 https://ror.org/03rc6as71 grid.24516.34 0000 0001 2370 4535 Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai, 201804 China
4 https://ror.org/00f54p054 grid.168010.e 0000 0004 1936 8956 Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305 USA
5 https://ror.org/035psfh38 grid.255169.c 0000 0000 9141 4786 Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620 China
6 https://ror.org/00g30e956 grid.9026.d 0000 0001 2287 2617 Center for Hybrid Nanostructures (CHyN), University of Hamburg, Hamburg, 20607 Germany
7 https://ror.org/02jz4aj89 grid.5012.6 0000 0001 0481 6099 Aachen Maastricht Institute for Biobased Materials, Maastricht University, RD Geleen, 6167 The Netherlands
17 9 2024
17 9 2024
2024
15 81725 12 2023
5 9 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/.
Nanocarriers (NCs) play a crucial role in delivering theranostic agents to tumors, making them a pivotal focus of research. However, the persistently low delivery efficiency of engineered NCs has been a significant challenge in the advancement of nanomedicine, stirring considerable debate. Transvascular transport is a critical pathway for NC delivery from vessels to tumors, yet a comprehensive understanding of the interactions between NCs and vascular systems remains elusive. In recent years, considerable efforts have been invested in elucidating the transvascular transport mechanisms of NCs, leading to promising advancements in tumor delivery and theranostics. In this context, we highlight various delivery mechanisms, including the enhanced permeability and retention effect, cooperative immune-driven effect, active transcytosis, and cell/bacteria-mediated delivery. Furthermore, we explore corresponding strategies aimed at enhancing transvascular transport of NCs for efficient tumor delivery. These approaches offer intriguing solutions spanning physicochemical, biological, and pharmacological domains to improve delivery and therapeutic outcomes. Additionally, we propose a forward-looking delivery framework that relies on advanced tumor/vessel models, high-throughput NC libraries, nano-bio interaction datasets, and artificial intelligence, which aims to guide the design of next-generation carriers and implementation strategies for optimized delivery.

Nanocarriers (NCs) are crucial in delivering therapeutic agents to tumors, and transvascular transport is a critical pathway for the tumor delivery of NCs. Here the authors summary strategies enhancing transvascular transport of NCs for efficient tumor delivery, and propose a delivery framework to guide the design of next-generation carriers and implementation strategies for optimized delivery.

Subject terms

Nanotechnology in cancer
Nanoparticles
Biomedical materials
https://doi.org/10.13039/501100001659 Deutsche Forschungsgemeinschaft (German Research Foundation) PAK961 PA749/21-2 Pich Andrij issue-copyright-statement© Springer Nature Limited 2024
==== Body
pmcIntroduction

The 2023 Nobel Prize in Physiology/Medicine brought great excitement to nanomedicine fields by recognizing the innovation of mRNA vaccines. During the COVID-19 pandemic, engineered nanocarriers (NCs) enabled the successful application of mRNA vaccines1. For intravenous administration, one goal of nanomedicine is to overcome multi-biological barriers in vivo for improving targeted delivery and theranostic efficacy2,3. For tumor delivery, NCs will encounter a series of biological barriers during blood circulation4, vascular extravasation5, tumor penetration6, cellular internalization and retention7. Among them, the vascular extravasation is a highly critical pathway for NC delivery into tumors, therefore the efficient NC delivery largely depends on tumor vascular systems8. In 1986, the enhanced permeability and retention (EPR) effect was postulated to explain the augment vascular extravasation and improved tumor delivery of NCs9,10. However, after 30 years of efforts, the clinical translation of such devised NCs according to the EPR effect is still low11,12. While there is evidence about the EPR effect in small animals such as mice, in fact, only a few nanomedicines are approved for clinical trials in humans13. Additionally, the statistical result from literature indicated that less than 1% of intravenously injected NCs can reach the tumor site in vivo14. Based on these disappointing facts, the availability of the EPR effect to tumor delivery of NCs has been seriously questioned in recent years15,16.

The basement membrane surrounding tumor vessels is an important but overlooked biological barrier for NC delivery based on the EPR effect17. After passing through the vascular endothelial gap, NCs may be trapped in the subendothelial space due to the dense basement membrane, which would hinder vascular extravasation of NCs into tumors. On the other hand, a research result showed that most of NCs are transvascularized into solid tumors by active transcytosis which may be a dominant mechanism for vascular extravasation18. In addition, several cells and bacteria were employed as Trojan Horses to carry NCs for improved transvascular transport and tumor delivery by their intrinsic inflammatory responsiveness or tumor-tropism or tumor-colonization properties19,20. These important discoveries of these mechanisms stimulated us to revisit the common approaches for tumor delivery of NCs.

Amidst the burgeoning understanding of cancer nanomedicine, pivotal discussions are underway regarding core concepts and effective approaches for the tumor delivery of NCs, with the aim of charting pathways toward enhanced clinical translation success. Firstly, the intricacy and diversity inherent in tumors and vessels necessitate patient stratification based on precise biomarkers. The patient stratification facilitates the customization of NC formulations, thereby optimizing personalized theranostics. Furthermore, in the realm of preclinical research, there is a pressing need to develop advanced tumor and vessel models that faithfully mimic human physiology, thereby superseding traditional animal models. Contemporary efforts in cancer nanomedicine extend beyond more NC formulation adjustments, now encompassing fundamental investigations into tumor biology and nano-bio interactions. Driven by the collection and analysis of nano-bio interaction data, a forward-looking guidance framework should be established to inform the design of NCs tailored for precise theranostics. In this review, we first compared the differences in the passive EPR effect and active transcytosis, and then summarized a variety of recent strategies for promoting vascular extravasation of NCs. Likewise, we also delve into the strategies of cell/bacterial-mediated delivery to bypass existing bottlenecks of transvascular transport for efficient NC delivery into tumors. Finally, the future and challenges of nanomedicine in clinical translation and applications are discussed. Noteworthy technological advancements poised to bolster the clinical translation of nanomedicines include organ-on-chip model, artificial intelligence (AI), high-throughput screening methodologies, and adept big data management practices. These innovations collectively hold promise in ushering nanomedicine from the realms of research to transformative clinical realities.

Passive EPR effect versus active transcytosis

Exploring the mechanism of NC delivery from vessel to tumor (i.e., vascular extravasation) is very important because this is a critical but incompletely understood pathway21. In general, vascular extravasation of NCs in tumor region can be mediated by passive EPR effect. The enhanced permeability arises from the large endothelial gaps or fenestrations in tumor vessels that allow the passage of NCs, and the enhanced retention results from a collapse of lymphatic drainage system where NCs cannot be transported away10,22. According to this mechanism, extensive efforts have been devoted to augment vascular extravasation by optimizing the physicochemical properties of engineered NCs, such as size/shape23, composition24, surface charge and modification25, as well as flexibility (Fig. 1a)26. Besides, the increased vascular extravasation of NCs can also be achieved by regulating the microenvironments of tumor vessels. Administration of anti-vascular endothelial growth factors (e.g., anti-VEGF or anti-VEGFR-2) can normalize vessels, thereby further augmenting the transvascular flux of NCs by the increased blood supply and decreased tumor interstitial fluid pressure (Fig. 1b)27. Vascular normalization can improve the extravasation of small sized NCs, however may impede the leakiness of larger NCs due to the reduced vascular permeability. Conversely, the vascular mediators, such as nitric oxide or angiotensin II, are able to improve vascular permeability for more effective extravasation of NCs (Fig. 1c)28. Likewise, exogenous assistance technologies including laser, magnetic, radiation and ultrasound offer encouraging tools to cause bursts or temporary pores in tumor vessels by photo-/magneto-thermal effect29,30, radiant energy31, or ultrasonic targeted microbubble destruction (UTMD)32 for boosting vascular extravasation of NCs (Fig. 1d). The latest insights indicate that the EPR effect will also vary with different stages of tumor development and treatment33. In general, the EPR effect is relatively significant in the early stage of tumors.Fig. 1 Strategies for improved vascular extravasation of nanocarriers (NCs) based on the EPR effect.

a Optimization of physicochemical properties of NCs; b Administration of anti-vascular endothelial growth factors for vascular normalization; c Administration of vascular mediators for increasing vascular permeability; d Exogenous assistance technologies for causing bursts or temporary pores of vessels. e After crossing the vascular endothelial cells, the NCs are trapped in the subendothelial void by basement membrane surrounding vessels, forming a perivascular NC pool that hinders their extravasation. Collagen hydrolase-mediated basement membrane destruction is used to increase NC extravasation. Another strategy—cooperative immune-driven strategy is proposed for increasing NC extravasation. Neutrophils bind to activated platelets (as recruitment beacons), subsequently migrating into the interior of NC pool through the cascade event including neutrophil adhesion on endothelium, crawling along endothelium, and diapedesis into NC pool. The neutrophil migration process can open the basement membrane barrier of NC pool and lead to the explosive pool eruption, thereby propelling the NCs deeper into tumors.

Recently, the contribution of passive EPR effect to tumor delivery of NCs has been mired in controversy due to several negative clinical trials. In 2023, it was found that the last line of defense for NC extravasation into tumors is not the vascular endothelial barrier, but a dense basement membrane surrounding the endothelium17. The basement membrane seriously hinders vascular extravasation of NCs by their entrapment in subendothelial void after crossing endothelial gap, forming a perivascular NC pool (Fig. 1e). Although collagen hydrolases are capable of degrading the basement membrane to release the trapped NCs34,35, this may also lead to irreversible destruction of basement membrane and increase the risk of cancer metastasis. Furthermore, a cooperative immune-driven strategy was developed, utilizing laser-mediated hyperthermia to induce inflammation which will recruit platelets and neutrophils (NEs) into NC pool. Through NE migration including endothelium adhesion, crawling and diapedesis, a dynamic window is temporarily created in basement membrane, thereby triggering NC pool eruptions and extravasation. The investigation not only explains the controversy over the EPR effect but also provides a different mechanism for the transvascular transport of NCs. In future research, it is worth considering whether the basement membrane uniformly surrounds the endothelium or exhibits the heterogeneity in different tumor vessels or vessel locations. In addition, previous work has already revealed that the EPR effect displays high heterogeneity in different species and tumor types36, which is not a general principle. There is indication, that the delivery is partly falsely claimed to be by the EPR effect, but instead is achieved by active transcytosis. A very recent work discovered that the frequency of endothelial gaps in tumor vessels is quite low (only 0.048% of vascular wall surface area) and thus insufficient for enhancing tumor delivery of NCs, contrary to the EPR effect18. Meanwhile, the results in mouse models and human specimens suggested that most of NCs are transported into solid tumors by active transcytosis of endothelial cells.

For now, both the passive EPR effect and active transcytosis are controversial in the community37,38. The heterogeneity between tumors and vessels affects the pathway of vascular extravasation of NCs. In 2023, a research work demonstrated that the EPR effect is still dominant for the tumors with high vascular permeability, while active transcytosis is the main mechanism of low-permeability tumor vessels39. Through ingenious design, they developed protein-based NCs for active transendothelial transport in low-permeability vessels by pinocytosis-mediated endocytosis and exocytosis, enabling the improved tumor delivery. Pinocytosis-mediated endocytosis is carried out through the extension of actin-stabilized plasma membranes to phagocytosis NCs, and then forming the macropinosome-based vesicles for their intracellular transfer7. As previously mentioned, the tumor delivery efficiency of NCs designed based on the EPR effect is low. The strategies based on active transcytosis or combined EPR effect and active transcytosis can overcome blood-tumor barrier to improve tumor delivery efficiency of NCs, and even promote the crossing of blood-brain barrier to increase NC accumulation in glioma. With such insights into tumor vascular extravasation of NCs, the criteria and strategy for the design of NCs might require some rethought, i.e. focus could be shifted from only considering NCs for passive EPR-mediated delivery to constructing NCs for augmented active transcytosis21.

Enhanced active transcytosis

Admittedly, little is known about the mechanism details of active transcytosis, especially what kind of characteristics of NCs may be more likely to trigger the transcytosis of endothelial cells. There is a series of previous works reporting transcytosis for the crossing of biological barriers40. The transcytosis of NCs is mainly based on caveolae-dependent endocytosis and exocytosis of vascular endothelial cells7. By invaginating the caveolin-coated plasma membrane, the caveolin-stabilized vesicle (i.e., caveolae) is formed for the endocytosis of NCs into endothelial cells. Subsequently, based on the caveolae-based shuttle mechanism, the NCs cross the vascular barrier. It has been reported that the surface engineering strategy of NCs (e.g., modification with specific ligands) is beneficial for promoting caveolae-dependent transcytosis by the interactions with the receptors on endothelium. Concerning delivery, active transcytosis triggered by ligand-receptor binding has been investigated to facilitate tumor vascular extravasation of NCs (Fig. 2a). For instance, albumin-bound drugs can induce caveolae-dependent transcytosis of vascular endothelial cells through the binding of the albumin and glycoprotein receptor on endothelial cells41. Moreover, tumor-penetrating peptides (e.g., iRGD) can be conjugated to NCs and then bind to αv integrins on tumor vascular endothelium42. Subsequently, the bound iRGD is cleaved by a protease into CendR fragments that can bind to overexpressed transmembrane glycoprotein of neuropilin-1 to induce caveolae-dependent transcytosis across vascular endothelial cells43, realizing direct delivery of NCs into tumors. Compared to iRGD-conjugated NCs, the co-administration of free iRGD with NCs shows higher transcytosis capacity as more receptors can be bound by free iRGD44.Fig. 2 Mechanism and heterogeneity of active transcytosis.

a Strategies for enhancing active transcytosis to facilitate the vascular extravasation of NCs, involving ligand-receptor triggered transcytosis (irradiation for precise regulation of receptor expression on endothelial cells), cationization triggered transcytosis, adsorption triggered transcytosis, and ultrasonic targeted microbubble destruction (UTMD) triggered transcytosis. b Location of special nanoparticle transport endothelial cells (N-TECs), rather than all endothelial cells, determines the vascular extravasation of NCs into tumors (purple area) and affects the distribution heterogeneity of NCs in tumor area, particularly with limited access in the area distant from N-TECs.

For ligand-receptor triggered transcytosis, the interferences with other cell surface receptors will result in off-target delivery, thereby reducing tumor delivery specificity and causing side effects45. Therefore, it is critical to achieve a high level of specific endothelial receptor expression on tumor vessels (Fig. 2a). In 2023, a spatiotemporal controllable aided strategy was proposed46, which is based on the use of low-dose X-ray irradiation to precisely regulate the expression of P-selectin in vascular endothelial cells of brain tumors. Then, fucoidan-based NCs can target highly expressed P-selectin on the activated endothelial cells, triggering caveolae-dependent transcytosis and overcoming the blood-brain barrier, resulting in more efficient and safe delivery to intracranial tumors47. The experimental data shows that the NCs localization in brain tumors in the experimental group increased more than threefold compared with the control group. Although active transcytosis of NCs does not significantly enhance drug delivery in brain tumors by orders of magnitude, it may have the potential to facilitate delivery across the blood-brain barrier46.

Apart from the strategy of ligand-receptor binding, cationization triggered transcytosis has also been developed for enhanced tumor delivery48. Once contacting tumor vascular endothelium, the overexpressed γ-glutamyl transpeptidase on endothelial cells induces charge cationization of γ-glutamyl transpeptidase-responsive polymers to facilitate caveolae-dependent endocytosis and transcytosis (Fig. 2a), leading to transendothelial and transcellular transport, as well as distribution throughout solid tumors49. Moreover, another strategy regarding adsorption triggered transcytosis was proposed (Fig. 2a)50. In this work, a polyzwitterion-based NC with protein non-stickiness and appropriate cellular affinity (i.e., reversible cell membrane binding ability) was designed. During blood circulation, non-stickiness towards proteins prolonged NC circulation time, subsequently NCs can bind reversibly to vascular endothelial cells and cancer cells due to their weak interaction with phospholipids. Compared to normal vascular endothelial cells, the adsorption of NCs on more active tumor vascular endothelial cells triggers rapid endocytosis and subsequent transcytosis. Adsorption triggered transcytosis is completed by caveolae-dependent endocytosis and macropinocytosis pathways for promoting the transendothelial and transcellular transport in tumors.

Moreover, some reports have implied that exogenous UTMD technology can not only temporarily increase vascular permeability and endothelial gaps51, but also promote the clathrin-dependent transcytosis of NCs (Fig. 2a)52. The clathrin-dependent transcytosis is the process of invaginating the plasma membrane to form vesicles through conformational changes in motor proteins, and utilizing intracellular actin to achieve cytoplasmic transport of vesicles and transvascular transport of NCs7. The increasing evidence shows that active transcytosis plays a key role in transvascular transport and tumor delivery of NCs50,53. To more effectively grasp the mechanism of active transcytosis, a deeper understanding of the interactions at the interface between NCs and vascular endothelium would be helpful.

Moreover, recent research has revealed the transvascular transport of NCs is not universally facilitated by all endothelial cells, but rather by a specific subset comprising approximately 21% termed nanoparticle transport endothelial cells (N-TECs). These N-TECs exhibit an uneven distribution along tumor vessels (Fig. 2b)54. Serving as gatekeepers, N-TECs exert significant influence over the vascular extravasation of NCs, their distribution, and their access to tumor regions. Gene expression profiling demonstrated that N-TECs present more genes related to vascular permeability and transport compared to other endothelial cells. From a fundamental standpoint, it is imperative to delve deeper into the molecular pathways governing transcytosis and elucidate the biological role of N-TECs. For instance, investigating whether additional endothelial cells can be induced to adopt the N-TEC phenotype is crucial. In terms of practical applications, attention should be directed towards discerning whether N-TECs can be manipulated to enhance NC extravasation into solid tumors and to explore their interactions with specific cancer or immune cells. Looking ahead, significant improvements in the efficiency of NC delivery to tumors could be achieved by optimizing the mechanism of active transcytosis, potentially by orders of magnitude. Such advancements would greatly enhance the clinical translation of nanomedicines by bolstering theranostic efficacy and mitigating side effects.

Cell/bacterial-mediated delivery

Cell-based systems

Over the past few years, a transpiring strategy is to exploit multiple types of living cells (e.g., red blood cells, monocytes, macrophages (MAs), NEs, T cells, mesenchymal and neural stem cells) to bypass the long-standing bottleneck of vascular barrier55–57. Each type of cell exhibits distinct advantages and preferred application scenarios3. Red blood cells bearing the surface self-marker CD47 endows them with excellent stealth property against the immune systems, thus obviously prolonging blood circulation time. Monocytes and MAs display diapedesis and chemotaxis toward the tumor microenvironments (e.g., hypoxia), and possess a natural ability to overcome the endothelial barriers, enabling the enhanced tumor delivery. The abundancy of NEs in blood allows them to accommodate large amounts of NCs, facilitating NC loading by phagocytosis or surface anchoring. The inflammatory microenvironments can actively recruit NEs to migrate across the endothelial barriers into inflamed tumors. Moreover, apart from being widely used in targeted immunotherapy of tumors, the main attraction of T cells as carrier is their ability to migrate toward inflammatory or lymphoid organs. Unlike the aforementioned circulating cells, mesenchymal and neural stem cells exhibit certain surface markers that endow them with tumor-tropic properties, thereby significantly improving tumor delivery. Different to the EPR effect and active transcytosis, living cells as Trojan Horses carrying NCs are able to improve transvascular transport and tumor delivery by utilizing cell-intrinsic properties (e.g., inflammatory-tropism, tumor-homing, tumor-infiltration, and immune evasion) (Fig. 3a, b). Circulating cells can adhere to the surface of activated endothelial cells, subsequently rolling and crawling alone vessels, which induces transvascular transport of cell-based systems58. Likewise, a large number of immune cells are also present in tumor tissues, called tumor-associated MAs or NEs, which have a positive impact on the continuous recruitment of circulating MA-/NE-based systems.Fig. 3 Cell- and bacterial-based systems for enhanced tumor delivery.

a Construction of cell-based systems, in which NCs are internalized by cells or are anchored on cellular surface. Preparation of biomimetic NCs for in situ cell hitchhiking based on enhanced cellular phagocytosis. b Two strategies for implementing transvascular delivery of cell-based systems (ex vivo preparation and in situ hitchhiking). Cell-based systems are guided by inflammatory factors (blue arrows) to infiltrate the inflamed tumor. Cell-based systems first adhere to activated vascular endothelium, and then roll and crawl along the endothelium, subsequently crossing the endothelial barrier into tumors by cell migration. In tumor region, the neutrophil extracellular traps (NETs) release and laser-induced photothermal ablation can disrupt cell carriers to trigger the release of NCs. c Construction of bacteria-based systems by bacterial internalization or surface adhesion of NCs. Through knocking out virulence genes or inactivating with laser to obtain attenuated strains as safe bacteria-based systems. d Bacteria-based systems for crossing vascular barrier in four ways: through transport across endothelial cells, by inducing cell damage or disrupting intercellular junctions, and in infected phagocytes. Subsequently, bacteria-based systems can also colonize in tumor due to the unique tumor microenvironments.

For the preparation of cell-based systems (Fig. 3a), NCs are taken up by cells due to their phagocytic nature (i.e., NC-internalized cell system)59, or are anchored on the cell surface by the specific binding (i.e., NC-anchored cell system)60. These cell-based systems may exhibit minimal immunogenicity and non-tumorigenicity. Among them, the NC-anchored cell system will still be affected by the exposed NCs, and further internalization of such NCs is inevitable. In addition, cell-based systems can also migrate into tumors and to metastatic cancer cells by responding to tumor-associated chemokines, which will effectively thwart tumor function and metastatic potential61,62. Note, that for all these benefits protocols for loading NCs into cells need to be optimized. The endocytosed NCs may in the worst case reduce cell viability, or change cell migratory behavior, which would impair tumor homing63. Likewise, NCs will not necessarily reside over extended periods of times in cells, and the respective contributions of exocytosis and proliferation need to be taken into account64. The release of NCs from cell-based systems in tumor region can be achieved by the exocytosis, neutrophil extracellular traps (NETs)-mediated cell disruption, or photothermal-mediated cell ablation. Furthermore, NCs may also be degraded in the endosomes/lysosomes of cell carriers65. For all those reasons, it is important to optimize the protocols around the expected time that NCs should remain biologically active. Apart from the loading protocols also the cells can be optimized. For example, genetically engineered cells exhibiting chemokine receptors (C-X-C chemokine receptor type 4 and C-C chemokine receptor type 2) and endothelial adhesion molecules (P-selectin glycoprotein ligand-1) are developed for targeted delivery66. The endothelial adhesion molecules are typically a type of selectin ligands or integrins that can bind to the overexpressed receptors on vascular endothelium (e.g., P selectin). The endothelial adhesion molecules of engineered cells can induce transient-cell tethering and rolling on the endothelium in disease region, which also promotes them exposure to specific chemokines displayed on endothelial surface, thus further binding to the chemokine receptors of engineered cells to activate a cascade of intracellular signaling responses. Subsequently, these bound cells undergo transvascular migration into the diseased tissue. Recently, some examples (e.g., neural stem cell-mediated 5-fluorocytosine prodrug) have been approved by the FDA for clinical trials to treat recurrent high-grade gliomas67.

Tumor development is often accompanied by inflammation, and immune cells will be continuously recruited into inflammation region of tumors68. Moreover, the amplification of inflammatory signals after surgery promotes cell-mediated tumor delivery58. After surgical tumor resection, the inflammation reaction occurs in brain, accompanied by the release of inflammatory factors, which activate the prepared NC-internalized NEs for migrating across vascular barrier into inflamed brain and improving brain tumor targeting (Fig. 3b)69. Compared to drug-loaded cationic liposomes, the use of NC-internalized NEs to deliver drug results in 86-fold higher drug concentrations in the brain. Remarkably, these immune cells are capable of activating the patient’s own immune systems to mount the antitumor response through immunotherapy.

Despite all the above examples, the impaired migratory capacity caused by low viability of reinjected living cell systems remains an unsolved difficulty70. Currently, a strategy was reported by bovine serum albumin-based NCs in situ hitchhiking activated living cells, which can overcome the limitations of ex vivo preparation of cell-based systems71. It was reported that the internalization of bovine serum albumin-based NCs by activated NEs in situ does not affect the mobility and the functions of cells. Some biomimetic NCs are beneficial for specific phagocytosis of cells in situ (Fig. 3a). Recently, a strategy of pathogen-mimicking nano-pathogenoids for hitchhiking NEs in situ was proposed72. The bacteria-secreted outer membrane vesicles (OMVs) containing pathogen-associated molecular patterns of native bacteria can used to coat NCs, that are effectively recognized and further internalized by NEs to form cell-based systems in vivo for enhanced delivery in inflamed tumor. Another vectorization strategy was developed to realize in vivo MAs-specific loading of NCs73. Cell-derived apoptotic bodies (ABs) as biological vehicles of NCs are readily engulfed by MAs74,75. After intravenous injection, ABs-encapsulated NCs can be rapidly phagocytized by MAs during blood circulation, leading to the enhanced tumor delivery by natural migratory and homing capacities of MAs. In a very recent work, a design criteria was reported to induce selective phagocytosis of NCs by NEs in vivo76. The interplay between agglutinated protein on NCs and complement proteins raises the potential to develop different approaches to immunotherapy77. Encouragingly, these strategies to promote NC phagocytosis by living cells are expected to address the bottleneck of high off-target phenomenon attributed to tumor heterogeneity19. Nevertheless, for cell-mediated delivery, the controlled release of NCs from cell carriers before and after their homing to tumors has always been the most challenging issue. Recent research showed that when NEs reach the inflammation region, they can be activated by the inflammatory microenvironments, and further form NETs within hours to facilitate the release of NCs from NEs69,78. Moreover, external triggers such as photothermal ablation of cell carriers may be one possible solution for controlled timing of release79.

Bacteria-based systems

In recent years, some bacteria (e.g., E. coli, S. typhimurium, L. monocytogenes, and L. lactis) have also been utilized as Trojan Horses to deliver NCs into tumors, by virtue of the ability of gene editing, tissue infiltration/colonization, and cell invasion80,81. Due to the low cultivation cost, high proliferative efficiency, and the natural ability to cross the vascular barrier, E. coli is widely used for targeted drug delivery. As another human symbiotic bacteria, L. lactis exhibits the tolerance to harsh gastrointestinal environments and the ability to colonize specific intestinal tissues. S. typhimurium enables tumor delivery by targeting hypoxic and necrotic areas of tumor, while the attenuated S. typhimurium can reduce the risk of septic shock, allowing it with an excellent safety. Unlike other bacteria, L. monocytogenes cannot replicate and spread in vivo and is often desirable as vaccine carriers. The bacteria can cross the blood-tumor barrier and even the blood-brain barrier in various ways: through transport across endothelial cells, by inducing cell damage or disrupting intercellular junctions, and in infected phagocytes (Fig. 3c, d)82. In general, the intracellular bacteria achieve transvascular transport through the pathways in infected phagocytes. Moreover, the extracellular bacteria can induce transcytosis of endothelial cells after adhesion to promote their delivery, or induce intracellular signaling pathways or produce cytolytic toxins leading to intercellular junction disruption or cell necrosis, thereby crossing the vascular barrier. Similar to cell-mediated delivery, inflammation also plays a central role in the transvascular transport of bacteria. The invasion of bacterial carriers will cause inflammation and result in the secretion of proinflammatory molecules, and this innate immune response can further increase vascular permeability (Fig. 3d)83. Meanwhile, bacteria are able to selectively colonize tumors due to the hypoxia and immunosuppressive tumor microenvironments, where bacteria circulating to normal tissues are eliminated, while those accumulated in tumors continue to proliferate84. However, the in vivo safety of bacteria-based systems is controversial due to the high proliferation and toxicity of bacteria, such as bacteremia. With the development of synthetic biology, gene engineering can be employed to knock out the major virulence genes to obtain attenuated strains (Fig. 3c)85. Additionally, different from pure bacterial carriers which will preserve a lot of residual bacteria after treatment, the residual bacteria can be effectively eliminated from the body after the treatment with bacterial-based systems86. A recent work indicated that the mineralized bacterial-based systems, i.e. the fixed bacteria coated with MnO2 nanoparticles, display more efficient tumor immunotherapy and safer in vivo use compared to pure bacterial carriers87.

Typically, in bacteria-based systems, the internalization is based on bacteria-specific ATP-binding cassette transporter or surface adhesion of NCs based on electrostatic interactions or covalent bonding (Fig. 3c)84,88. The former is a complete Trojan Horses system and can avoid the damage of surface adhered NCs to the bacterial capsule. In 2022, the attenuated facultatively anaerobic bacteria (S. typhimurium and E. coli) were utilized to uptake indocyanine green-based nanoparticles by the ATP-binding cassette transporter pathway86. The prepared bacterial-based system displays the hypoxia-targeting ability to overcome the blood-brain barrier and achieve deep penetration for enhanced glioma treatment. Excitingly, both bacteria and nanoparticles are present in significantly higher amounts in the brain compared to other organs, which may be due to the selective proliferation of bacteria in the unique glioma microenvironments including hypoxia, immunosuppression and biochemical properties. Upon the irradiation of near-infrared laser, the photothermal effect can ablate tumor cells and promote the release of tumor-associated antigens, while it also lyses bacterial cells and facilitates the release of various pathogen-associated molecular patterns, thus eliciting potent antitumor immunity. Besides, anaerobic bacteria possess the capability to specifically colonize the hypoxic tumor region as oxygen concentration gradients guide them to migrate towards hypoxic microenvironments89.

Although the attenuated bacteria are capable of reducing the risk of septic shock in the host, any retained virulence may cause problems for immunocompromised patients90. In 2023, through inactivating with UV irradiation (Fig. 3c), a supposedly safe dead E. coli-based system was developed to improve tumor delivery of NCs without potential bacterial toxicity as they retain the intact structure and chemotaxis of E. coli while losing the capacity of proliferation and pathogenicity91. After intravenous injection, the dead E. coli-based system can efficiently deliver nanotherapeutics to the brain for the treatment of bacterial meningitis and glioma. More importantly, the dead E. coli-based system exhibits a high biosafety in vivo. Even with high injected dose (~1 ×109 CFU), all mice are still alive after 14 days. As a comparison, when the injected dose of living E. coli is only 1 ×106 CFU, all mice are dead after 5 days owing to their severe pathogenicity.

It is worth mentioning that unlike conventional delivery systems, the engineering bacteria with vast gene packaging capacity can also in situ produce active drugs, such as nucleic acids, peptides, proteins, or enzymes for the treatment of tumors92,93. Nevertheless, the regulation of expression levels and extracellular delivery of these active drugs has not been effectively addressed. Further investigations are needed to integrate these therapeutically engineered bacteria with NCs for targeted delivery and theranostics of tumors. Moreover, a small amount of literature has shown that the accumulation of bacterial carriers in various organs in vivo (mainly liver and kidney) can be completed cleared within 1-2 weeks, but the systematic description of the whole process of bacterial fate in vivo is missing, which is also an issue that cannot be ignored for further clinical transformation of bacterial carriers.

Challenges of clinical translation

As our understanding of tumor delivery of NCs continues to evolve, innovative NCs have been meticulously engineered to surmount the vascular barrier. Regrettably, many of these studies merely serve as proof-of-concept demonstrations, lacking quantitative comparisons against existing methodologies. Consequently, it is likely that numerous newly developed delivery routes are not inherently more efficient than their predecessors. Furthermore, the bulk of research endeavors tend to focus solely on biomedical applications of NCs from the vantage point of their chemical design, neglecting the practical clinical requirements and engineering challenges associated with material preparation. This glaring disparity between the proliferation of nanoplatforms and their limited clinical translation has sparked intense debate94. Moving beyond the strategies discussed above, a change in research culture and advancement in key technologies may usher in a different guiding delivery framework, thereby catalyzing substantive progress in cancer nanomedicine (Fig. 4). Different from previously reported frameworks for designing delivery systems95, the framework proposed here highlights the importance of assembling high-quality datasets and optimizing NCs-vascular system interactions through the utilization of machine learning and AI tools. Particularly, it emphasizes the need to account for tumor/vessel heterogeneity and patient stratification. Concurrently, this framework advocates for the formulation of standardized guidelines for nanomedicine and the establishment of an NC library to address issues such as poor reproducibility of data results and the repetitive implementation of validation work, respectively.Fig. 4 Dataset collection of nano-bio interactions using interdisciplinary tools.

Statistics-based artificial intelligence (AI) analysis provides tools to correlate multiple parameters between nano-bio interactions, such as NC characteristics, tumor/vessel models, vascular parameters, tumor accumulation, delivery efficiency, and therapeutic outcome. A prospective guiding framework for personalizing the design of effective NCs for precise theranostics of specific tumors. First, the pathophysiology of tumor, vessel, and patient is analyzed, as well as the experiment datasets are from standardized manual. Second, the information and delivery goals are used as input of a computer algorithm, which is based on the established datasets of nano-bio interactions. Third, the specification of NC design and the selection of assistant strategy are the output. Fourth, injection of appropriate NCs dose with/without adjuvants is performed along with the clinical performance and therapeutic effects monitoring of NCs. Fifth, clinically validated NCs are incorporated into the library, and fed back to AI for dataset calibration.

Tumor/vessel models and patient stratification

The complexity and heterogeneity of human tumors/vessels and preclinical animal models are a major cause of the poor clinical translation of NCs96. A recognized obstacle is the lack of tumor models that can recapitulate human cancers for preclinical nanomedicine research97. Currently, humanized orthotopic tumors are constructed in animal models to allow the investigation of NCs in more physiologically relevant tumor development, but their complexity hinders testing based on large screening98. It is encouraging that the developed organ-on-chip models may simultaneously address these challenges, including preclinical models to recapitulate human biology and tumor heterogeneity, as well as high-throughput testing99,100. In a recent work, a vasculature-on-chip model was engineered to dissect the role of flow rate and shear stress in vascular endothelial transcytosis of NCs101. In 2023, an AI-assisted single vessel quantitative analysis method (nanoISML) was developed and then quantified more than 67000 individual vessels from 32 tumor models, revealing the highly heterogeneous transvascular transport of NCs39. This method can effectively classify the vascular permeability and assist in the rational design of NCs.

Moreover, patient stratification is also urgently needed to match the heterogeneity of cancer patients with specific NC formulations102,103. Some researchers are trying to establish the biomarkers for patient stratification11,104. For instance, immunohistochemistry is employed to assess specific or highly expressed biomarkers (e.g., receptors or antigens) on tumors and vessels. Besides, circulating tumor cell analysis can also be exploited for patient stratification. Medical diagnostic technologies, such as magnetic resonance, positron emission tomography, or single-photon emission computed tomography imaging, not only monitor the biomarker expression on tumors and vessels for stratification of metastatic patients, but also obtain the detailed information on the intuitive biodistribution and accumulation of the labeled NCs for screening responsive patients. A recent study proposed a method based on histopathological biomarkers that can predict the NC accumulation in tumors by scoring the density of tumor vessels and tumor-associated macrophages, thus providing a powerful and straightforward protocol for patient stratification in clinical trials105. However, the development of more diagnostic biomarkers and tools with precise sensitivity and universality for patient stratification is still a challenge in cancer nanomedicine104. It is expected that once the challenge is resolved, the clinical translation rate of nanomedicines will be greatly improved.

Standardization of preclinical research

The clinical translation of nanomedicine has been plagued by different synthesis methods, various physicochemical properties of NCs, inconsistent characterization in vitro/in vivo, and disappointing experimental reproducibility. To unify these operations, a standardized manual of nanomedicines should be drafted106. Although the Minimum Information Reporting in Bio-Nano Experimental Literature (MIRIBEL) provides some guidelines107, there have been claims that it cannot meet the requirements of NC diversity and has therefore received inconsistent opinions108. Actually, the current literature, even in the same field, is lacking standardized guidance, which is detrimental to experiment data reproducibility, quantitative comparison, meta-analysis, and modeling.

Nano-bio interaction collection based on interdisciplinary tools

For the development of NCs in tumor delivery and theranostic applications, the current guiding framework is based on a trial-and-error strategy: 1) preparation of NCs, 2) characterization at cell level and animal models, and 3) evaluation of delivery efficiency and theranostic outcomes95. The standardized screening of NC myriad is unrealistic. Therefore, we should shift the focus from the preparation of versatile NCs (engineering perspective) to the exploration of basic relationship between NCs and vascular system interactions (biological perspective), which is critical to determine the optimal design of NCs for highly efficient tumor delivery109,110. Nevertheless, it is a complex set of interactions defined by multiple property parameters, such as NC characteristics34,111, injected NC dose112, tumor types113, blood velocity114, vessel architecture95, vessel density115, vessel perfusion116, vessel permeability53, and immune cell composition117. Examples to date have been limited to one or a few interaction between NCs and vascular system.

The integration of AI and big data management is able to facilitate multivariate research and complex relationship analysis to build predictive models for optimizing the design of NCs118,119. A prominent example is the exploitation of DNA barcoding and sequencing to achieve the testing data of a large number of NCs in same experimental animal120,121. Moreover, a high-throughput screening approach (nanoPRISM) was proposed to systematically evaluate the interactions between 35 different nanoparticle types (including core composition, surface chemistry and size parameters) and hundreds of cancer cell lines122. This approach can screen the key factors for cell internalization of NCs, thereby accelerating the rational design of NCs for specific cell types and reducing the requirement for preclinical animal experiments. Although this work only focused on cellular internalization of NCs, it is exciting that this approach can easily be expanded to investigate the relationship between NC properties and transvascular transport. For example, this approach is integrated with organ-on-chip models to simulate transvascular processes and then collect the nano-bio interaction data. Together, the development of these AI technologies will bring the promise of nanomedicine closer to reality. Moreover, such AI technology is supported by the new policies of the FDA118, and the personalized tumor radiotherapy powered by AI has been clinically successful123. Therefore, the high-quality datasets of NCs-vascular system interactions defined by computer technology will provide a forward-thinking and brand-new guiding delivery framework, that is, to design personalized NCs and delivery strategies for specific patients124,125.

NC library

Finally, an authoritative and publicly available library of nanomedicines should be created to collect the NCs that have been validated in preclinical and clinical trials. The researchers or industries should submit the information regarding NC formulations, tumor/vessel models, and implementation proposals. Furthermore, the independent third-party organizations and governments should validate NC properties, nano-bio interactions, delivery efficiency, and therapeutic efficacy according to the standard nanomedicine guidelines. Finally, the governments should establish a reliable NC library. The library will not only avoid a lot of repetitive verification work, but also guide the design of the next-generation NCs.

Perspectives

In summary, we are gaining a deeper understanding of the opportunities and challenges presented by transvascular transport and tumor delivery of NCs. Different insights into cancer nanomedicine will change the NC design and tumor theranostics, and further promote the clinical translation of NCs. First, the vascular basement membrane, as an insurmountable biological barrier, limits the EPR effect. For this long-neglected barrier, more engineered strategies need to be developed to overcome it. Besides, it is crucial to strike a balance between transvascular transport of NCs and transvascular metastasis of cancer cells, which will occur with the removal of basement membrane. An ideal strategy to overcome the basement membrane barrier is to enhance transvascular delivery while avoiding cancer metastasis. In addition, the EPR effect should not be considered as a dogma in tumor delivery of NCs, and the active transcytosis mechanism may be regarded as an important route for transvascular transport. However, for active transcytosis, a lot of unknown work needs to be explored to reveal the detailed endocytosis and transcytosis process (especially the biological role of N-TECs), as well as the interactions between NCs and vascular systems. Besides, the tumor progression and microenvironments also have an impact on transvascular transport of NCs3. For instance, during tumor progression, the extracellular matrix becomes highly unregulated and disorganized, leading to tumor fibrosis or tumor vascularization downregulation. The stromal cells and immunosuppressive environments of tumors play important roles in regulating angiogenesis-related markers and genes. By modulating tumor microenvironments, such as reducing the extracellular matrix, or decreasing the interstitial fluid pressure, or disrupting stromal cells, or optimizing immune cells, the vascular permeability can be improved and the transvascular transport of NCs can be facilitated. Remarkably, cell/bacterial-mediated delivery provides the pathways to cross the vascular barrier and overcome the long-standing bottleneck of NC delivery into tumors. Meanwhile, the detailed research is needed on the unique functions of different types of cells or bacteria as well as their mechanisms of targeted tumor delivery. These emerging bioinspired strategies may be essential to drive further progress of cancer nanomedicine. When choosing or designing one suitable strategy to improve transvascular delivery, the following four aspects should be considered: 1) the biosafety and clinical accessibility, 2) the precise targeting of tumor vascular endothelium, 3) the efficiency of transvascular transport, and 4) the inhibitory effect of cancer transvascular metastasis.

In addition, the guiding framework for NC delivery into tumors still remains changing. For the dilemma of tumor/vessel complexity and heterogeneity, the protocols for patient stratification are urgently needed to select the beneficial patients for nanotheranostics. Generally, the biomarkers and clinical imaging techniques can be employed to screen for responsive patients, thereby optimizing the therapeutic efficacy of nanomedicines. In preclinical experiments, animal models should be added on humanized orthotopic tumor/vessel models. Moreover, the development of organ-on-chip models can not only obtain preclinical models that are close to human physiology, but also reveal and collect a large amount of data on NCs-vascular system interactions by high-throughput testing. Meanwhile, the integration with machine learning and AI technologies enables the execution of complex multiparameter studies, thereby establishing predictive models to guide the design of NCs. The implementation guidelines of MIRIBEL would in a first attempt able to standardize preclinical research of nanomedicine, and thus facilitating experiment reproducibility, quantitative comparisons, and meta-analyses. Still, in the future a more widely agreed-on guideline would be helpful. Many of these approaches are performed according to a trial-and-error strategy that verifies the effectiveness of the designed NCs through a complicated experimental process. Recently, we have re-examined the focus on tumor delivery of NCs from the engineering to the biological perspective. A forward-looking guiding framework is proposed based on the collection and analysis of complex interactions of NCs-vascular systems by the interdisciplinary tools and developments, including advanced tumor/vessel models, high-throughput NC libraries, big data management, and AI. Once sufficient high-quality nano-bio interaction datasets are established, one can guide the design of improved NC properties and delivery strategies by computer algorithms according to the biological indicators of a specific cancer patient. We can foresee that these in-depth recognitions of NC delivery into tumors can facilitate the transition of nanomedicines from bench to bedside.

Acknowledgements

This research was financially supported by the Deutsche Forschungsgemeinschaft (DFG) (PA 794/21-2 and PAK961) (W.P. and A.P.), the Collaborative Research Center (SFB 985, Functional Microgels and Microgel Systems) (A.P.), the Shanghai Pujiang Program (23PJ1412900) (X.L.), the National Natural Science Foundation of China (NSFC) (52373154, 52103181) (Y.H.), the NSFC Excellent Senior Scientist Program (A.P.), and the NSFC Excellent Young Scientist Program (overseas) (Y.H.). Part of figures was created partially utilizing the templates on https://smart.servier.com/ as a reference.

Author contributions

X.L., X.Z., W.P. and A.P. conceived the manuscript format. X.L. and A.P. wrote the initial manuscript. X.L. designed the figures. All authors edited the manuscript.

Peer review

Peer review information

Nature Communications thanks Paolo Decuzzi, Irene de Lazaro, Hirak Patra and Jin Xie for their contribution to the peer review of this work. A peer review file is available.

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. Callaway E Naddaf M Pioneers of mRNA COVID vaccines win medicine Nobel Nature 2023 622 228 229 10.1038/d41586-023-03046-x 37783956
Callaway, E. & Naddaf, M. Pioneers of mRNA COVID vaccines win medicine Nobel. Nature 622, 228–229 (2023).37783956
2. Peer D Nanocarriers as an emerging platform for cancer therapy Nat. Nanotechnol. 2007 2 751 760 10.1038/nnano.2007.387 18654426
Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).18654426
3. Izci M Maksoudian C Manshian BB Soenen SJ The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors Chem. Rev. 2021 121 1746 1803 10.1021/acs.chemrev.0c00779 33445874
Izci, M., Maksoudian, C., Manshian, B. B. & Soenen, S. J. The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors. Chem. Rev. 121, 1746–1803 (2021).33445874
4. Parodi A Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions Nat. Nanotechnol. 2013 8 61 68 10.1038/nnano.2012.212 23241654
Parodi, A. et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotechnol. 8, 61–68 (2013).23241654
5. Xue XD Trojan Horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment Nat. Commun. 2018 9 3653 10.1038/s41467-018-06093-5 30194413
Xue, X. D. et al. Trojan Horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment. Nat. Commun. 9, 3653 (2018).30194413
6. Jang HL Sengupta S Transcellular transfer of nanomedicine Nat. Nanotechnol. 2019 14 731 732 10.1038/s41565-019-0494-y 31263193
Jang, H. L. & Sengupta, S. Transcellular transfer of nanomedicine. Nat. Nanotechnol. 14, 731–732 (2019).31263193
7. Donahue ND Acar H Wilhelm S Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine Adv. Drug Deliv. Rev. 2019 143 68 96 10.1016/j.addr.2019.04.008 31022434
Donahue, N. D., Acar, H. & Wilhelm, S. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Adv. Drug Deliv. Rev. 143, 68–96 (2019).31022434
8. Locard-Paulet M Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration Sci. Signal. 2016 9 ra15 10.1126/scisignal.aac5820 26861043
Locard-Paulet, M. et al. Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration. Sci. Signal. 9, ra15 (2016).26861043
9. Gerlowski LE Jain RK Microvascular permeability of normal and neoplastic tissues Microvasc. Res. 1986 31 288 305 10.1016/0026-2862(86)90018-X 2423854
Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).2423854
10. Matsumura Y Maeda H A New Concept For Macromolecular Therapeutics In Cancer-Chemotherapy - Mechanism Of Tumoritropic Accumulation Of Proteins And The Antitumor Agent Smancs Cancer Res. 1986 46 6387 6392 2946403
Matsumura, Y. & Maeda, H. A New Concept For Macromolecular Therapeutics In Cancer-Chemotherapy - Mechanism Of Tumoritropic Accumulation Of Proteins And The Antitumor Agent Smancs. Cancer Res. 46, 6387–6392 (1986).2946403
11. Shi JJ Kantoff PW Wooster R Farokhzad OC Cancer nanomedicine: progress, challenges and opportunities Nat. Rev. Cancer 2017 17 20 37 10.1038/nrc.2016.108 27834398
Shi, J. J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).27834398
12. He HL Liu LS Morin EE Liu M Schwendeman A Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures Acc. Chem. Res. 2019 52 2445 2461 10.1021/acs.accounts.9b00228 31424909
He, H. L., Liu, L. S., Morin, E. E., Liu, M. & Schwendeman, A. Survey of Clinical Translation of Cancer Nanomedicines-Lessons Learned from Successes and Failures. Acc. Chem. Res. 52, 2445–2461 (2019).31424909
13. Zhou Q Tumor Abnormality-Oriented Nanomedicine Design Chem. Rev. 2023 123 10920 10989 10.1021/acs.chemrev.3c00062 37713432
Zhou, Q. et al. Tumor Abnormality-Oriented Nanomedicine Design. Chem. Rev. 123, 10920–10989 (2023).37713432
14. Wilhelm S Analysis of nanoparticle delivery to tumours Nat. Rev. Mater. 2016 1 16014 10.1038/natrevmats.2016.14
Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).
15. Nel A Ruoslahti E Meng H New Insights into “Permeability” as in the Enhanced Permeability and Retention Effect of Cancer Nanotherapeutics ACS Nano 2017 11 9567 9569 10.1021/acsnano.7b07214 29065443
Nel, A., Ruoslahti, E. & Meng, H. New Insights into “Permeability” as in the Enhanced Permeability and Retention Effect of Cancer Nanotherapeutics. ACS Nano 11, 9567–9569 (2017).29065443
16. Chan WCW Nanomedicine 2.0 Acc. Chem. Res. 2017 50 627 632 10.1021/acs.accounts.6b00629 28945418
Chan, W. C. W. Nanomedicine 2.0. Acc. Chem. Res. 50, 627–632 (2017).28945418
17. Wang, Q. et al. Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours. Nat. Nanotechnol., 10.1038/s41565-023-01498 (2023).
18. Sindhwani S The entry of nanoparticles into solid tumours Nat. Mater. 2020 19 566 575 10.1038/s41563-019-0566-2 31932672
Sindhwani, S. et al. The entry of nanoparticles into solid tumours. Nat. Mater. 19, 566–575 (2020).31932672
19. Zhang ZW Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis Adv. Funct. Mater. 2018 28 1801840 10.1002/adfm.201801840
Zhang, Z. W. et al. Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis. Adv. Funct. Mater. 28, 1801840 (2018).
20. Jiang W Designing nanomedicine for immuno-oncology Nat. Biomed. Eng. 2017 1 0029 10.1038/s41551-017-0029
Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1, 0029 (2017).
21. Pandit S Dutta D Nie SM Active transcytosis and new opportunities for cancer nanomedicine Nat. Mater. 2020 19 478 480 10.1038/s41563-020-0672-1 32332990
Pandit, S., Dutta, D. & Nie, S. M. Active transcytosis and new opportunities for cancer nanomedicine. Nat. Mater. 19, 478–480 (2020).32332990
22. Maeda H Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity Adv. Drug Deliv. Rev. 2015 91 3 6 10.1016/j.addr.2015.01.002 25579058
Maeda, H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv. Rev. 91, 3–6 (2015).25579058
23. Wang S Huang P Chen XY Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization Adv. Mater. 2016 28 7340 7364 10.1002/adma.201601498 27255214
Wang, S., Huang, P. & Chen, X. Y. Hierarchical Targeting Strategy for Enhanced Tumor Tissue Accumulation/Retention and Cellular Internalization. Adv. Mater. 28, 7340–7364 (2016).27255214
24. Mitchell MJ Engineering precision nanoparticles for drug delivery Nat. Rev. Drug Discov. 2021 20 101 124 10.1038/s41573-020-0090-8 33277608
Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).33277608
25. Li ZM Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration Adv. Sci. 2021 8 2002589 10.1002/advs.202002589
Li, Z. M. et al. Applications of Surface Modification Technologies in Nanomedicine for Deep Tumor Penetration. Adv. Sci. 8, 2002589 (2021).
26. Li Z Influence of nanomedicine mechanical properties on tumor targeting delivery Chem. Soc. Rev. 2020 49 2273 2290 10.1039/C9CS00575G 32215407
Li, Z. et al. Influence of nanomedicine mechanical properties on tumor targeting delivery. Chem. Soc. Rev. 49, 2273–2290 (2020).32215407
27. Chauhan VP Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner Nat. Nanotechnol. 2012 7 383 388 10.1038/nnano.2012.45 22484912
Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7, 383–388 (2012).22484912
28. Seki T Fang J Maeda H Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application Cancer Sci. 2009 100 2426 2430 10.1111/j.1349-7006.2009.01323.x 19793083
Seki, T., Fang, J. & Maeda, H. Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application. Cancer Sci. 100, 2426–2430 (2009).19793083
29. Feng C Germanene-Based Theranostic Materials for Surgical Adjuvant Treatment: Inhibiting Tumor Recurrence and Wound Infection Matter 2020 3 127 144 10.1016/j.matt.2020.04.022
Feng, C. et al. Germanene-Based Theranostic Materials for Surgical Adjuvant Treatment: Inhibiting Tumor Recurrence and Wound Infection. Matter 3, 127–144 (2020).
30. Liu JF Use of Oppositely Polarized External Magnets To Improve the Accumulation and Penetration of Magnetic Nanocarriers into Solid Tumors ACS Nano 2020 14 142 152 10.1021/acsnano.9b05660 31854966
Liu, J. F. et al. Use of Oppositely Polarized External Magnets To Improve the Accumulation and Penetration of Magnetic Nanocarriers into Solid Tumors. ACS Nano 14, 142–152 (2020).31854966
31. Miller MA Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts Sci. Transl. Med. 2017 9 eaal0225 10.1126/scitranslmed.aal0225 28566423
Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 9, eaal0225 (2017).28566423
32. Guo YT Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles Sci. Adv. 2021 7 eabf7390 10.1126/sciadv.abf7390 33931452
Guo, Y. T. et al. Single-cell analysis reveals effective siRNA delivery in brain tumors with microbubble-enhanced ultrasound and cationic nanoparticles. Sci. Adv. 7, eabf7390 (2021).33931452
33. Gawne, P. J., Ferreira, M., Papaluca, M., Grimm, J. & Decuzzi, P. New opportunities and old challenges in the clinical translation of nanotheranostics. Nat. Rev. Mater.10.1038/s41578-023-00581-x (2023).
34. Blanco E Shen H Ferrari M Principles of nanoparticle design for overcoming biological barriers to drug delivery Nat. Biotechnol. 2015 33 941 951 10.1038/nbt.3330 26348965
Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).26348965
35. Jain RK Stylianopoulos T Delivering nanomedicine to solid tumors Nat. Rev. Clin. Oncol. 2010 7 653 664 10.1038/nrclinonc.2010.139 20838415
Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).20838415
36. Nichols JW Bae YH EPR: Evidence and fallacy J. Controlled Rel. 2014 190 451 464 10.1016/j.jconrel.2014.03.057
Nichols, J. W. & Bae, Y. H. EPR: Evidence and fallacy. J. Controlled Rel. 190, 451–464 (2014).
37. Nuhn L Artificial intelligence assists nanoparticles to enter solid tumours Nat. Nanotechnol. 2023 18 550 551 10.1038/s41565-023-01382-7 37081083
Nuhn, L. Artificial intelligence assists nanoparticles to enter solid tumours. Nat. Nanotechnol. 18, 550–551 (2023).37081083
38. Sun R The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives Adv. Drug Deliv. Rev. 2022 191 114614 10.1016/j.addr.2022.114614 36347432
Sun, R. et al. The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives. Adv. Drug Deliv. Rev. 191, 114614 (2022).36347432
39. Zhu M Machine-learning-assisted single-vessel analysis of nanoparticle permeability in tumour vasculatures Nat. Nanotechnol. 2023 18 657 666 10.1038/s41565-023-01323-4 36781994
Zhu, M. et al. Machine-learning-assisted single-vessel analysis of nanoparticle permeability in tumour vasculatures. Nat. Nanotechnol. 18, 657–666 (2023).36781994
40. Rothen-Rutishauser B Clift MJD Jud C Fink A Wick P Human epithelial cells in vitro - Are they an advantageous tool to help understand the nanomeaterial-biological barrier interaction? Eur. Nanotox Lett. 2012 4 1 20 10.1515/entl-2015-0004
Rothen-Rutishauser, B., Clift, M. J. D., Jud, C., Fink, A. & Wick, P. Human epithelial cells in vitro - Are they an advantageous tool to help understand the nanomeaterial-biological barrier interaction? Eur. Nanotox Lett. 4, 1–20 (2012).
41. Von Hoff DD Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine N. Engl. J. Med. 2013 369 1691 1703 10.1056/NEJMoa1304369 24131140
Von Hoff, D. D. et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).24131140
42. Ruoslahti E Tumor penetrating peptides for improved drug delivery Adv. Drug Deliv. Rev. 2017 110 3 12 10.1016/j.addr.2016.03.008 27040947
Ruoslahti, E. Tumor penetrating peptides for improved drug delivery. Adv. Drug Deliv. Rev. 110, 3–12 (2017).27040947
43. Kadonosono T Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation J. Controlled Rel. 2015 201 14 21 10.1016/j.jconrel.2015.01.011
Kadonosono, T. et al. Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation. J. Controlled Rel. 201, 14–21 (2015).
44. Sugahara KN Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs Science 2010 328 1031 1035 10.1126/science.1183057 20378772
Sugahara, K. N. et al. Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science 328, 1031–1035 (2010).20378772
45. Terstappen GC Meyer AH Bell RD Zhang W Strategies for delivering therapeutics across the blood-brain barrier Nat. Rev. Drug Discov. 2021 20 362 383 10.1038/s41573-021-00139-y 33649582
Terstappen, G. C., Meyer, A. H., Bell, R. D. & Zhang, W. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 20, 362–383 (2021).33649582
46. Tylawsky DE P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis Nat. Mater. 2023 22 391 399 10.1038/s41563-023-01481-9 36864161
Tylawsky, D. E. et al. P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis. Nat. Mater. 22, 391–399 (2023).36864161
47. Shamay Y P-selectin is a nanotherapeutic delivery target in the tumor microenvironment Sci. Transl. Med. 2018 10 345ra387
Shamay, Y. et al. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci. Transl. Med. 10, 345ra387 (2018).
48. Zhou Q Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy Nat. Nanotechnol. 2019 14 799 809 10.1038/s41565-019-0485-z 31263194
Zhou, Q. et al. Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol. 14, 799–809 (2019).31263194
49. Wang GW Enzyme-Triggered Transcytosis of Dendrimer-Drug Conjugate for Deep Penetration into Pancreatic Tumors ACS Nano 2020 14 4890 4904 10.1021/acsnano.0c00974 32286784
Wang, G. W. et al. Enzyme-Triggered Transcytosis of Dendrimer-Drug Conjugate for Deep Penetration into Pancreatic Tumors. ACS Nano 14, 4890–4904 (2020).32286784
50. Chen SQ Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity Nat. Biomed. Eng. 2021 5 1019 10.1038/s41551-021-00701-4 33859387
Chen, S. Q. et al. Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity. Nat. Biomed. Eng. 5, 1019 (2021).33859387
51. Jia L Ultrasound-enhanced precision tumor theranostics using cell membrane-coated and pH-responsive nanoclusters assembled from ultrasmall iron oxide nanoparticles Nano Today 2021 36 101022 10.1016/j.nantod.2020.101022
Jia, L. et al. Ultrasound-enhanced precision tumor theranostics using cell membrane-coated and pH-responsive nanoclusters assembled from ultrasmall iron oxide nanoparticles. Nano Today 36, 101022 (2021).
52. Delalande A Leduc C Midoux P Postema M Pichon C Efficient Gene Delivery By Sonoporation Is Associated With Microbubble Entry Into Cells And The Clathrin-Dependent Endocytosis Pathway Ultrasound Med. Biol. 2015 41 1913 1926 10.1016/j.ultrasmedbio.2015.03.010 25929996
Delalande, A., Leduc, C., Midoux, P., Postema, M. & Pichon, C. Efficient Gene Delivery By Sonoporation Is Associated With Microbubble Entry Into Cells And The Clathrin-Dependent Endocytosis Pathway. Ultrasound Med. Biol. 41, 1913–1926 (2015).25929996
53. Matsumoto Y Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery Nat. Nanotechnol. 2016 11 533 538 10.1038/nnano.2015.342 26878143
Matsumoto, Y. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 11, 533–538 (2016).26878143
54. Kingston BR Specific Endothelial Cells Govern Nanoparticle Entry into Solid Tumors ACS Nano 2021 15 14080 14094 10.1021/acsnano.1c04510 34382779
Kingston, B. R. et al. Specific Endothelial Cells Govern Nanoparticle Entry into Solid Tumors. ACS Nano 15, 14080–14094 (2021).34382779
55. Wang Q Non-genetic engineering of cells for drug delivery and cell-based therapy Adv. Drug Deliv. Rev. 2015 91 125 140 10.1016/j.addr.2014.12.003 25543006
Wang, Q. et al. Non-genetic engineering of cells for drug delivery and cell-based therapy. Adv. Drug Deliv. Rev. 91, 125–140 (2015).25543006
56. Anselmo AC Mitragotri S Cell-mediated delivery of nanoparticles: Taking advantage of circulatory cells to target nanoparticles J. Controlled Rel. 2014 190 531 541 10.1016/j.jconrel.2014.03.050
Anselmo, A. C. & Mitragotri, S. Cell-mediated delivery of nanoparticles: Taking advantage of circulatory cells to target nanoparticles. J. Controlled Rel. 190, 531–541 (2014).
57. Batrakova EV Gendelman HE Kabanov AV Cell-mediated drug delivery Expert Opin. Drug Deliv. 2011 8 415 433 10.1517/17425247.2011.559457 21348773
Batrakova, E. V., Gendelman, H. E. & Kabanov, A. V. Cell-mediated drug delivery. Expert Opin. Drug Deliv. 8, 415–433 (2011).21348773
58. Kolaczkowska E Kubes P Neutrophil recruitment and function in health and inflammation Nat. Rev. Immunol. 2013 13 159 175 10.1038/nri3399 23435331
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).23435331
59. Zhang WZ Nanoparticle-Laden Macrophages for Tumor-Tropic Drug Delivery Adv. Mater. 2018 30 1805557 10.1002/adma.201805557
Zhang, W. Z. et al. Nanoparticle-Laden Macrophages for Tumor-Tropic Drug Delivery. Adv. Mater. 30, 1805557 (2018).
60. Stephan MT Moon JJ Um SH Bershteyn A Irvine DJ Therapeutic cell engineering with surface-conjugated synthetic nanoparticles Nat. Med. 2010 16 1035 1041 10.1038/nm.2198 20711198
Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).20711198
61. de Visser KE Eichten A Coussens LM Paradoxical roles of the immune system during cancer development Nat. Rev. Cancer 2006 6 24 37 10.1038/nrc1782 16397525
de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 24–37 (2006).16397525
62. Kitamura T Qian BZ Pollard JW Immune cell promotion of metastasis Nat. Rev. Immunol. 2015 15 73 86 10.1038/nri3789 25614318
Kitamura, T., Qian, B. Z. & Pollard, J. W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 15, 73–86 (2015).25614318
63. Nold P Optimizing conditions for labeling of mesenchymal stromal cells (MSCs) with gold nanoparticles: a prerequisite for in vivo tracking of MSCs J. Nanobiotechnol. 2017 15 24 10.1186/s12951-017-0258-5
Nold, P. et al. Optimizing conditions for labeling of mesenchymal stromal cells (MSCs) with gold nanoparticles: a prerequisite for in vivo tracking of MSCs. J. Nanobiotechnol. 15, 24 (2017).
64. Kang YA Quantitative considerations about the size dependence of cellular entry and excretion of colloidal nanoparticles for different cell types Chemtexts 2022 8 9 10.1007/s40828-021-00159-6 35223376
Kang, Y. A. et al. Quantitative considerations about the size dependence of cellular entry and excretion of colloidal nanoparticles for different cell types. Chemtexts 8, 9 (2022).35223376
65. Kreyling WG In vivo integrity of polymer-coated gold nanoparticles Nat. Nanotechnol. 2015 10 619 623 10.1038/nnano.2015.111 26076469
Kreyling, W. G. et al. In vivo integrity of polymer-coated gold nanoparticles. Nat. Nanotechnol. 10, 619–623 (2015).26076469
66. Wang H Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue Nat. Biomed. Eng. 2022 6 882 897 10.1038/s41551-021-00815-9 34931077
Wang, H. et al. Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue. Nat. Biomed. Eng. 6, 882–897 (2022).34931077
67. Aboody KS Neural Stem Cell-Mediated Enzyme/Prodrug Therapy for Glioma: Preclinical Studies Sci. Transl. Med. 2013 5 184ra159 10.1126/scitranslmed.3005365
Aboody, K. S. et al. Neural Stem Cell-Mediated Enzyme/Prodrug Therapy for Glioma: Preclinical Studies. Sci. Transl. Med. 5, 184ra159 (2013).
68. Hanahan D Coussens LM Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Cancer Cell 2012 21 309 322 10.1016/j.ccr.2012.02.022 22439926
Hanahan, D. & Coussens, L. M. Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment. Cancer Cell 21, 309–322 (2012).22439926
69. Xue JW Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence Nat. Nanotechnol. 2017 12 692 700 10.1038/nnano.2017.54 28650441
Xue, J. W. et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat. Nanotechnol. 12, 692–700 (2017).28650441
70. Di Domizio J Gilliet M Designer cells finely tuned for therapy Science 2015 350 1478 1479 10.1126/science.aad9464 26680184
Di Domizio, J. & Gilliet, M. Designer cells finely tuned for therapy. Science 350, 1478–1479 (2015).26680184
71. Chu DF Gao J Wang ZJ Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection ACS Nano 2015 9 11800 11811 10.1021/acsnano.5b05583 26516654
Chu, D. F., Gao, J. & Wang, Z. J. Neutrophil-Mediated Delivery of Therapeutic Nanoparticles across Blood Vessel Barrier for Treatment of Inflammation and Infection. ACS Nano 9, 11800–11811 (2015).26516654
72. Li M Chemotaxis-driven delivery of nano-pathogenoids for complete eradication of tumors post-phototherapy Nat. Commun. 2020 11 1126 10.1038/s41467-020-14963-0 32111847
Li, M. et al. Chemotaxis-driven delivery of nano-pathogenoids for complete eradication of tumors post-phototherapy. Nat. Commun. 11, 1126 (2020).32111847
73. Zheng LY In Vivo Monocyte/Macrophage-Hitchhiked Intratumoral Accumulation of Nanomedicines for Enhanced Tumor Therapy J. Am. Chem. Soc. 2020 142 382 391 10.1021/jacs.9b11046 31801020
Zheng, L. Y. et al. In Vivo Monocyte/Macrophage-Hitchhiked Intratumoral Accumulation of Nanomedicines for Enhanced Tumor Therapy. J. Am. Chem. Soc. 142, 382–391 (2020).31801020
74. Akers JC Gonda D Kim R Carter BS Chen CC Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies J. Neuro Oncol. 2013 113 1 11 10.1007/s11060-013-1084-8
Akers, J. C., Gonda, D., Kim, R., Carter, B. S. & Chen, C. C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J. Neuro Oncol. 113, 1–11 (2013).
75. Palma M 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. Immunother. 2012 61 865 879 10.1007/s00262-011-1149-5 22086161
Palma, M. et al. 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. Immunother. 61, 865–879 (2012).22086161
76. Myerson JW Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation Nat. Nanotechnol. 2022 17 86 97 10.1038/s41565-021-00997-y 34795440
Myerson, J. W. et al. Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation. Nat. Nanotechnol. 17, 86–97 (2022).34795440
77. Kim J Sahay G Nanomedicine hitchhikes on neutrophils to the inflamed lung Nat. Nanotechnol. 2022 17 1 2 10.1038/s41565-021-00981-6 34795439
Kim, J. & Sahay, G. Nanomedicine hitchhikes on neutrophils to the inflamed lung. Nat. Nanotechnol. 17, 1–2 (2022).34795439
78. Che JY Neutrophils Enable Local and Non-Invasive Liposome Delivery to Inflamed Skeletal Muscle and Ischemic Heart Adv. Mater. 2020 32 2003598 10.1002/adma.202003598
Che, J. Y. et al. Neutrophils Enable Local and Non-Invasive Liposome Delivery to Inflamed Skeletal Muscle and Ischemic Heart. Adv. Mater. 32, 2003598 (2020).
79. Anbrosone A Control of Wnt/beta-Catenin Signaling Pathway in Vivo via Light Responsive Capsules ACS Nano 2016 10 4828 4834 10.1021/acsnano.5b07817 26799662
Anbrosone, A. et al. Control of Wnt/beta-Catenin Signaling Pathway in Vivo via Light Responsive Capsules. ACS Nano 10, 4828–4834 (2016).26799662
80. Zhou Y Han Y Engineered bacteria as drug delivery vehicles: Principles and prospects Eng. Microbiol. 2022 2 100034 10.1016/j.engmic.2022.100034
Zhou, Y. & Han, Y. Engineered bacteria as drug delivery vehicles: Principles and prospects. Eng. Microbiol. 2, 100034 (2022).
81. Coureuil M Lecuyer H Bourdoulous S Nassif X A journey into the brain: insight into how bacterial pathogens cross blood-brain barriers Nat. Rev. Microbiol. 2017 15 149 159 10.1038/nrmicro.2016.178 28090076
Coureuil, M., Lecuyer, H., Bourdoulous, S. & Nassif, X. A journey into the brain: insight into how bacterial pathogens cross blood-brain barriers. Nat. Rev. Microbiol. 15, 149–159 (2017).28090076
82. Le Guennec L Coureuil M Nassif X Bourdoulous S Strategies used by bacterial pathogens to cross the blood-brain barrier Cell. Microbiol. 2020 22 e13132 10.1111/cmi.13132 31658405
Le Guennec, L., Coureuil, M., Nassif, X. & Bourdoulous, S. Strategies used by bacterial pathogens to cross the blood-brain barrier. Cell. Microbiol. 22, e13132 (2020).31658405
83. Sellner J Leib SL In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9/TIMP-1 ratio and increased collagen type IV degradation Neurobiol. Dis. 2006 21 647 656 10.1016/j.nbd.2005.09.007 16257222
Sellner, J. & Leib, S. L. In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9/TIMP-1 ratio and increased collagen type IV degradation. Neurobiol. Dis. 21, 647–656 (2006).16257222
84. Chen F Nanophotosensitizer-engineered Salmonella bacteria with hypoxia targeting and photothermal-assisted mutual bioaccumulation for solid tumor therapy Biomaterials 2019 214 119226 10.1016/j.biomaterials.2019.119226 31174068
Chen, F. et al. Nanophotosensitizer-engineered Salmonella bacteria with hypoxia targeting and photothermal-assisted mutual bioaccumulation for solid tumor therapy. Biomaterials 214, 119226 (2019).31174068
85. Forbes NS Engineering the perfect (bacterial) cancer therapy Nat. Rev. Cancer 2010 10 784 793 10.1038/nrc2934
Forbes, N. S. Engineering the perfect (bacterial) cancer therapy. Nat. Rev. Cancer 10, 784–793 (2010).
86. Sun R Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy Nat. Commun. 2022 13 5127 10.1038/s41467-022-32837-5 36050316
Sun, R. et al. Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy. Nat. Commun. 13, 5127 (2022).36050316
87. Wang, C. et al. Oncolytic mineralized bacteria as potent locally administered immunotherapeutics. Nat. Biomed. Eng.10.1038/s41551-024-01191-w (2024).
88. Tang J Multifunctional nanoagents for ultrasensitive imaging and photoactive killing of Gram-negative and Gram-positive bacteria Nat. Commun. 2019 10 4057 10.1038/s41467-019-12088-7 31492849
Tang, J. et al. Multifunctional nanoagents for ultrasensitive imaging and photoactive killing of Gram-negative and Gram-positive bacteria. Nat. Commun. 10, 4057 (2019).31492849
89. Chen W Bacteria-Driven Hypoxia Targeting for Combined Biotherapy and Photothermal Therapy ACS Nano 2018 12 5995 6005 10.1021/acsnano.8b02235 29786420
Chen, W. et al. Bacteria-Driven Hypoxia Targeting for Combined Biotherapy and Photothermal Therapy. ACS Nano 12, 5995–6005 (2018).29786420
90. Zhou S Gravekamp C Bermudes D Liu K Tumour-targeting bacteria engineered to fight cancer Nat. Rev. Cancer 2018 18 727 743 10.1038/s41568-018-0070-z 30405213
Zhou, S., Gravekamp, C., Bermudes, D. & Liu, K. Tumour-targeting bacteria engineered to fight cancer. Nat. Rev. Cancer 18, 727–743 (2018).30405213
91. Lu J Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier Nano Lett. 2023 23 4326 4333 10.1021/acs.nanolett.3c00563 37130058
Lu, J. et al. Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier. Nano Lett. 23, 4326–4333 (2023).37130058
92. Wang L Cao Z Zhang M Lin S Liu J Spatiotemporally Controllable Distribution of Combination Therapeutics in Solid Tumors by Dually Modified Bacteria Adv. Mater. 2022 34 2106669 10.1002/adma.202106669
Wang, L., Cao, Z., Zhang, M., Lin, S. & Liu, J. Spatiotemporally Controllable Distribution of Combination Therapeutics in Solid Tumors by Dually Modified Bacteria. Adv. Mater. 34, 2106669 (2022).
93. Raman V Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases Nat. Commun. 2021 12 6116 10.1038/s41467-021-26367-9 34675204
Raman, V. et al. Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases. Nat. Commun. 12, 6116 (2021).34675204
94. van der Meel R Lammers T Hennink WE Cancer nanomedicines: oversold or underappreciated? Expert Opin. Drug Deliv. 2017 14 1 5 10.1080/17425247.2017.1262346 27852113
van der Meel, R., Lammers, T. & Hennink, W. E. Cancer nanomedicines: oversold or underappreciated? Expert Opin. Drug Deliv. 14, 1–5 (2017).27852113
95. Poon W Kingston BR Ouyang B Ngo W Chan WCW A framework for designing delivery systems Nat. Nanotechnol. 2020 15 819 829 10.1038/s41565-020-0759-5 32895522
Poon, W., Kingston, B. R., Ouyang, B., Ngo, W. & Chan, W. C. W. A framework for designing delivery systems. Nat. Nanotechnol. 15, 819–829 (2020).32895522
96. Hrkach J Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile Sci. Transl. Med. 2012 4 128ra139 10.1126/scitranslmed.3003651
Hrkach, J. et al. Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile. Sci. Transl. Med. 4, 128ra139 (2012).
97. Sharpless NE DePinho RA Model organisms - The mighty mouse: genetically engineered mouse models in cancer drug development Nat. Rev. Drug Discov. 2006 5 741 754 10.1038/nrd2110 16915232
Sharpless, N. E. & DePinho, R. A. Model organisms - The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741–754 (2006).16915232
98. Landgraf M McGovern JA Friedl P Hutmacher DW Rational Design of Mouse Models for Cancer Research Trends Biotechnol. 2018 36 242 251 10.1016/j.tibtech.2017.12.001 29310843
Landgraf, M., McGovern, J. A., Friedl, P. & Hutmacher, D. W. Rational Design of Mouse Models for Cancer Research. Trends Biotechnol. 36, 242–251 (2018).29310843
99. Albanese A Lam AK Sykes EA Rocheleau JV Chan WCW Tumour-on-a-chip provides an optical window into nanoparticle tissue transport Nat. Commun. 2013 4 2718 10.1038/ncomms3718 24177351
Albanese, A., Lam, A. K., Sykes, E. A., Rocheleau, J. V. & Chan, W. C. W. Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat. Commun. 4, 2718 (2013).24177351
100. Wang HF Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation ACS Nano 2018 12 11600 11609 10.1021/acsnano.8b06846 30380832
Wang, H. F. et al. Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation. ACS Nano 12, 11600–11609 (2018).30380832
101. Chen YY Syed AM MacMillan P Rocheleau JV Chan WCW Flow Rate Affects Nanoparticle Uptake into Endothelial Cells Adv. Mater. 2020 32 e1906274 10.1002/adma.201906274 32383233
Chen, Y. Y., Syed, A. M., MacMillan, P., Rocheleau, J. V. & Chan, W. C. W. Flow Rate Affects Nanoparticle Uptake into Endothelial Cells. Adv. Mater. 32, e1906274 (2020).32383233
102. Cheng ZL Al Zaki A Hui JZ Muzykantov VR Tsourkas A Multifunctional Nanoparticles: Cost Versus Benefit of Adding Targeting and Imaging Capabilities Science 2012 338 903 910 10.1126/science.1226338 23161990
Cheng, Z. L., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional Nanoparticles: Cost Versus Benefit of Adding Targeting and Imaging Capabilities. Science 338, 903–910 (2012).23161990
103. Cabral H Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size Nat. Nanotechnol. 2011 6 815 823 10.1038/nnano.2011.166 22020122
Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotechnol. 6, 815–823 (2011).22020122
104. van der Meel R Smart cancer nanomedicine Nat. Nanotechnol. 2019 14 1007 1017 10.1038/s41565-019-0567-y 31695150
van der Meel, R. et al. Smart cancer nanomedicine. Nat. Nanotechnol. 14, 1007–1017 (2019).31695150
105. May, J.-N. et al. Histopathological biomarkers for predicting the tumour accumulation of nanomedicines. Nat. Biomed. Eng.10.1038/s41551-024-01197-4 (2024).
106. Lammers T Storm G Setting standards to promote progress in bio-nano science Nat. Nanotechnol. 2019 14 626 626 10.1038/s41565-019-0497-8 31270443
Lammers, T. & Storm, G. Setting standards to promote progress in bio-nano science. Nat. Nanotechnol. 14, 626–626 (2019).31270443
107. Faria M Minimum information reporting in bio-nano experimental literature Nat. Nanotechnol. 2018 13 777 785 10.1038/s41565-018-0246-4 30190620
Faria, M. et al. Minimum information reporting in bio-nano experimental literature. Nat. Nanotechnol. 13, 777–785 (2018).30190620
108. Leong HS On the issue of transparency and reproducibility in nanomedicine Nat. Nanotechnol. 2019 14 629 635 10.1038/s41565-019-0496-9 31270452
Leong, H. S. et al. On the issue of transparency and reproducibility in nanomedicine. Nat. Nanotechnol. 14, 629–635 (2019).31270452
109. de Lazaro I Mooney DJ Obstacles and opportunities in a forward vision for cancer nanomedicine Nat. Mater. 2021 20 1469 1479 10.1038/s41563-021-01047-7 34226688
de Lazaro, I. & Mooney, D. J. Obstacles and opportunities in a forward vision for cancer nanomedicine. Nat. Mater. 20, 1469–1479 (2021).34226688
110. Bai X Toward a systematic exploration of nano-bio interactions Toxicol. Appl. Pharmacol. 2017 323 66 73 10.1016/j.taap.2017.03.011 28344110
Bai, X. et al. Toward a systematic exploration of nano-bio interactions. Toxicol. Appl. Pharmacol. 323, 66–73 (2017).28344110
111. Zhou Q Tumor extravasation and infiltration as barriers of nanomedicine for high efficacy: The current status and transcytosis strategy Biomaterials 2020 240 119902 10.1016/j.biomaterials.2020.119902 32105817
Zhou, Q. et al. Tumor extravasation and infiltration as barriers of nanomedicine for high efficacy: The current status and transcytosis strategy. Biomaterials 240, 119902 (2020).32105817
112. Ouyang B The dose threshold for nanoparticle tumour delivery Nat. Mater. 2020 19 1362 10.1038/s41563-020-0755-z 32778816
Ouyang, B. et al. The dose threshold for nanoparticle tumour delivery. Nat. Mater. 19, 1362 (2020).32778816
113. Sykes EA Tailoring nanoparticle designs to target cancer based on tumor pathophysiology Proc. Natl Acad. Sci. USA 2016 113 E1142 E1151 10.1073/pnas.1521265113 26884153
Sykes, E. A. et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology. Proc. Natl Acad. Sci. USA 113, E1142–E1151 (2016).26884153
114. Thurber, G. M. & Weissleder, R. A Systems Approach for Tumor Pharmacokinetics. Plos One 6, 10.1371/journal.pone.0024696 (2011).
115. Ekdawi SN Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model J. Controlled Rel. 2015 207 101 111 10.1016/j.jconrel.2015.04.006
Ekdawi, S. N. et al. Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model. J. Controlled Rel. 207, 101–111 (2015).
116. Stirland DL Matsumoto Y Toh K Kataoka K Bae YH Analyzing spatiotemporal distribution of uniquely fluorescent nanoparticles in xenograft tumors J. Controlled Rel. 2016 227 38 44 10.1016/j.jconrel.2016.02.016
Stirland, D. L., Matsumoto, Y., Toh, K., Kataoka, K. & Bae, Y. H. Analyzing spatiotemporal distribution of uniquely fluorescent nanoparticles in xenograft tumors. J. Controlled Rel. 227, 38–44 (2016).
117. Cuccarese MF Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging Nat. Commun. 2017 8 14293 10.1038/ncomms14293 28176769
Cuccarese, M. F. et al. Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging. Nat. Commun. 8, 14293 (2017).28176769
118. Topol EJ High-performance medicine: the convergence of human and artificial intelligence Nat. Med. 2019 25 44 56 10.1038/s41591-018-0300-7 30617339
Topol, E. J. High-performance medicine: the convergence of human and artificial intelligence. Nat. Med. 25, 44–56 (2019).30617339
119. Yamankurt G Exploration of the nanomedicine-design space with high-throughput screening and machine learning Nat. Biomed. Eng. 2019 3 318 327 10.1038/s41551-019-0351-1 30952978
Yamankurt, G. et al. Exploration of the nanomedicine-design space with high-throughput screening and machine learning. Nat. Biomed. Eng. 3, 318–327 (2019).30952978
120. Yaari, Z. et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nat. Commun. 7, 10.1038/ncomms13325 (2016).
121. Paunovska K A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation Nano Lett. 2018 18 2148 2157 10.1021/acs.nanolett.8b00432 29489381
Paunovska, K. et al. A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation. Nano Lett. 18, 2148–2157 (2018).29489381
122. Boehnke N Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery Science 2022 377 eabm5551 10.1126/science.abm5551 35862544
Boehnke, N. et al. Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery. Science 377, eabm5551 (2022).35862544
123. Chamunyonga C Edwards C Caldwell P Rutledge P The Impact of Artificial Intelligence and Machine Learning in Radiation Therapy: Considerations for Future Curriculum Enhancement J. Med. Imaging Radiat. Sci. 2020 51 214 220 10.1016/j.jmir.2020.01.008 32115386
Chamunyonga, C., Edwards, C., Caldwell, P. & Rutledge, P. The Impact of Artificial Intelligence and Machine Learning in Radiation Therapy: Considerations for Future Curriculum Enhancement. J. Med. Imaging Radiat. Sci. 51, 214–220 (2020).32115386
124. Paunovska K Loughrey D Sago CD Langer R Dahlman JE Using Large Datasets to Understand Nanotechnology Adv. Mater. 2019 31 e1902798 10.1002/adma.201902798 31429126
Paunovska, K., Loughrey, D., Sago, C. D., Langer, R. & Dahlman, J. E. Using Large Datasets to Understand Nanotechnology. Adv. Mater. 31, e1902798 (2019).31429126
125. Lazarovits J Supervised Learning and Mass Spectrometry Predicts the in Vivo Fate of Nanomaterials ACS Nano 2019 13 8023 8034 10.1021/acsnano.9b02774 31268684
Lazarovits, J. et al. Supervised Learning and Mass Spectrometry Predicts the in Vivo Fate of Nanomaterials. ACS Nano 13, 8023–8034 (2019).31268684
