
==== Front
J Nanobiotechnology
J Nanobiotechnology
Journal of Nanobiotechnology
1477-3155
BioMed Central London

39285458
2844
10.1186/s12951-024-02844-3
Review
The biomedical applications of nanozymes in orthopaedics based on regulating reactive oxygen species
Gao Xiangcheng 1
Zhang Jiejie 2
Gong Yining gong_yn@163.com

1
Yan Liang yanliangdr5583@163.com

1
1 https://ror.org/017zhmm22 grid.43169.39 0000 0001 0599 1243 Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi 710061 China
2 https://ror.org/015ycqv20 grid.452702.6 0000 0004 1804 3009 Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000 China
16 9 2024
16 9 2024
2024
22 56926 6 2024
7 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/.
Nanozymes, a category of nanomaterials with enzyme-like activity, have garnered growing interest in various biomedical contexts. Notably, nanozymes that are capable of regulating reactive oxygen species levels by emulating antioxidant or prooxidant enzymes within cells hold significant therapeutic potential for a range of disorders. Herein, we overview the catalytic mechanisms of four exemplary nanozymes within the orthopedic domain. Subsequently, we emphasize recent groundbreaking advancements in nanozyme applications in orthopaedics, encompassing osteoarthritis, osteoporosis, intervertebral disc degeneration, bone defects, spinal cord injury, gout, rheumatoid arthritis, osteosarcoma and bone infection. Furthermore, we discuss the emerging area’s future prospects and several noteworthy challenges in biomedical application. This review not only fosters the ongoing development of nanozyme research but also fosters the emergence of more potent nanozymes for the treatment of orthopaedical diseases in the future.

Keywords

Bone tissue engineering
Biomedical applications
Nanozymes
Orthopaedics
Reactive oxygen species
National Natural Science Foundation of China82260181 Key project of Natural Science Basic Research Plan of Shaanxi Province2022JZ-43 National Key Research and Development Program of China2022YFC2407503 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Nanozymes are a class of nanomaterials with enzyme-like characteristics. In 2007, Yan and co-workers first reported the intrinsic peroxidase-like activity of magnetic nanoparticles (Fe3O4 NPs) and their catalytic mechanism and function were similar to those of natural horseradish peroxidase (HRP) [1]. In 2013, Wang et al. defined nanozymes as nanomaterials with enzyme-like activities [2]. As the field progresses, nanozymes came to be defined as nanomaterials that catalyze the conversion of enzyme substrates to products under physiologically relevant conditions and follow enzymatic kinetics such as Michaelis–Menten kinetics, even though the molecular mechanisms of the reactions could be different between nanozymes and the corresponding natural enzymes [3, 4]. In 2022, Nanozymes were announced as the 2022 top ten chemical emerging technologies by the International Union of Pure and Applied Chemistry (IUPAC). Nanozymes have both the physicochemical properties of nanomaterials and catalytic function similar to those of nature enzymes, with the benefits of both [5, 6]. Its nanostructure not only endows nanozymes with extremely effective catalytic activity but also renders them more stable and easier to mass production [2, 7]. Up to now, many kinds of nanozymes with various activities have been developed. Therefore, with the merits of multienzyme-like activity, tunable catalytic activity, high stability, simple preparation, low cost, and mass production potentials, nanozymes are promising alternatives for natural enzymes and have wide applications in numerous fields, including environmental protection [8, 9], biosensing [10, 11], chemical analysis [6, 12], and disease diagnosis and therapy [13, 14].

So far, numerous nanomaterials have been founded to mimic the catalytic activity of nature enzymes such as metals [15, 16], metal oxides [17], metal-organic frameworks (MOFs) [18, 19], carbons [20, 21]. Analogous to natural enzymes, nanozymes can be classified into the following four categories based on their catalytic activities: oxidoreductase-, hydrolase-, isomerase-, and synthases-like nanozymes [5, 7]. Among these, oxidoreductase-like nanozymes are a large family that was the earliest founded and most extensively developed, including oxidase (OXD)-, peroxidase (POD)-, catalase (CAT)-, and superoxide dismutase (SOD)-like nanozymes [22]. Significantly, nanozymes with antioxidant-like activity play a central role in safeguarding cells from the harmful impact of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which is vital for the treatment of various diseases [23, 24]. Beyond displaying antioxidant-like activity, nanozymes with prooxidant-like activity capable of producing ROS also possess therapeutic implications owing to their capacity to induce oxidative damage, hence eliminating bacteria or cancer cells [25].

Actually, ROS mainly includes superoxide anion (O2•−), hydrogen peroxide (H2O2), singlet oxygen (1O2), and hydroxyl radical (•OH) [26]. In real physiological environment, it is a double-edged sword for biomass. On the one hand, ROS participate in phenomena that traverse all of biology, playing an important role in regulating various physiological functions of living organisms [27]. A basal level of ROS can act as second messenger, which is necessary for basic biological processes such as cellular proliferation and differentiation [28]. On the other hand, excessive ROS leads to oxidative stress that is implicated in a variety of diseases, such as cancer [29], neurodegenerative diseases [30, 31], cardiovascular diseases [32], inflammation [33], etc. Thus, eliminating ROS by employing antioxidant strategies or stimulating ROS production by prooxidants endogenous to the body is vital for preserving normal physiological functioning. Traditional methods for ROS regulation predominantly rely on redox enzymes or small molecule drugs; however, these approaches often fail to fully address clinical requirements. In contrast, nanozymes present a distinctive advantage in ROS regulation due to their high and sustained catalytic activity, which is attributed to their stable structure and numerous catalytic sites. Furthermore, many nanozymes are capable of exhibiting diverse biocatalytic functions by modulating their internal nanostructure or altering their external environment. Notably, nanozymes can also engage in self-cascade catalysis, a phenomenon that is challenging to replicate with conventional enzymes or small molecules. Importantly, nanozymes may demonstrate remotely controlled catalytic activity in response to external stimuli, such as light, ultrasound, and magnetic fields. Therefore, nanozymes can be used to treat orthopaedical diseases by leveraging their biocatalytic activity in regulating ROS.

In recent years, a variety of nanozymes have been found to have endogen-like antioxidant activities, such as SOD-like nanozymes [34], CAT-like nanozymes [35] and glutathione peroxidase (GPx) -like nanozymes [36], allowing them to catalyze ROS/organic hydroperoxides to generate H2O/alcohols. Moreover, some nanozymes with the ability to mimic POD activity have been observed to decompose H2O2, generating free radicals, and some nanozymes with the ability to mimic OXD activity, which convert O2 to ROS. Another advantage of nanozymes is that some nanozymes can exhibit magnetic properties, photothermal properties, electrical properties and fluorescent behavior for biosensing, imaging, and therapy of various diseases [37]. Therefore, nanozymes hold promise in regulating ROS levels and may serve as a valuable therapeutic tool.

In this review, we focused on the biomedical application of the nanozyme in orthopaedics. First, we examine the catalytic mechanisms of SOD, CAT, GPx, and POD-like nanozymes (Scheme 1). Then, we highlight the recent representative advances of nanozymes in orthopaedics. The symptoms covered in the review include degenerative disease (osteoarthritis, osteoporosis, intervertebral disc degeneration), traumatic diseases (bone defect and spine cord injury), immuno-inflammatory diseases (gout and rheumatoid arthritis) and infect and neoplastic diseases (osteosarcoma and bone infection) (Scheme 2). We anticipate that this timely review will not only boost the further development of nanozyme research but also promote the development of more effective nanozymes for the treatment of orthopaedical diseases in the future.

Scheme 1 Schematic representation of the main enzyme-like activities of nanozymes

Scheme 2 Schematic illustration indicating the catalytic mechanism of nanozymes and the application of nanozymes in major orthopaedical disorders

The catalytic mechanisms of nanozymes

The catalytic mechanism of nanozymes can be influenced by the type of enzyme-like catalytic reactions, the type of reactants, and the type of nanomaterials [6]. Most nanozymes are capable of triggering changes in ROS levels, such as SOD, CAT, GPx and POD -like nanozymes. Given that nearly all nanozymes reported for orthopaedic disease theranostics exhibit these diverse activities, we primarily focus on discussing the catalytic mechanisms of the four key nanozymes.

SOD‑like nanozymes

Superoxide dismutase (SOD), an endogenous antioxidant enzyme present in human body, plays a vital role in cellular defense against oxidative damage caused by ROS [38]. It is categorized into four types based on the metal cofactor, including Cu/Zn SOD, Fe SOD, Mn SOD and Ni SOD [39]. Drawing inspiration from natural SOD, researchers have discovered over 100 types of nanozymes that exhibit SOD-like activity. These nanozymes predominantly consist of transition metals such as Cu, Fe, Mn, Co, Ce, Pt, Ru, as well as other metals, oxides, carbides, nitrides, and sulfides. Similar to natural SOD, SOD-like nanozymes can also catalyze the dismutation of O2•− to produce H2O2 and O2. Furthermore, most SOD-like nanozymes also possess CAT activity, enabling them to further decompose the resulting H2O2 into H2O and O2. In other words, these nanozymes can effectively eliminate excess ROS and RNS from organisms, making them more promising than natural SOD or other small antioxidant molecules. Therefore, SOD-like nanozymes play a significant role in the treatment of ROS-related diseases in orthopaedics. For example, utilized for its SOD-mimicking activity, attributed to its superior biocompatibility and negligible toxicity [40]. Generally, cerium can be found in two oxidation states: Ce3+ and Ce4+. The mechanism behind CeO2’s ability to scavenge O2•− is believed to arise from the interconversion between Ce3+ and Ce4+, concurrent with the development and translocation of oxygen vacancies. Specifically, the nanoparticles convert O2•− into H2O2, while Ce3+ is oxidized to Ce4+; subsequent to which Ce4+ and H2O2 react to regenerate Ce3+ and oxidize H2O2 back to O2 [41]. Consequently, the amalgamation of reactions involving O2•− and H2O2 represents a remarkably efficient antioxidant function, rendering CeO2 exceedingly appealing as a biological antioxidant.

CAT‑like nanozymes

Catalase (CAT), an enzyme responsible for the degradation of hydrogen peroxide in living organisms, plays a crucial protective role by detoxifying ROS [42]. Natural CAT enzymes consist of four iron-containing heme moieties, enabling them to efficiently break down H2O2 into H2O and O2, which can protect cells from oxidative stress damage by reducing the accumulation of H2O2 [43]. However, the high cost, environmental sensitivity, and instability of natural CAT enzymes limit their applications. Fortunately, the discovery of CAT-like nanozymes has provided a breakthrough. These nanozymes mimic the function of CAT and its catalytic mechanism is characterized by a straightforward process involving redox reactions and adsorption activation and the catalytic reaction follows the well-known Michaelis-Menten kinetics. Similar to natural CAT, CAT-like nanozymes can also catalyze the dismutation of H2O2 to produce H2O and O2 [35]. Furthermore, they can improve the hypoxic environment of certain cells by generating O2. Researchers have identified various nanomaterials with remarkable CAT-like activity, including Mn, Fe, Cu, Ce, Ir, and Pt, as well as oxides, sulfides, and carbonitrides of metals such as Mn, Fe, Ru, and Mo. Additionally, some CAT-like nanozymes exhibit synergistic effects with SOD-like activity, effectively regulating cellular H2O2 levels and mitigating oxidative injury.

For instance, CeO2 is known for its high intrinsic CAT activity, efficiently decomposing H2O2 into H2O and O2. The fast and convenient oxidation state transition from Ce3+ to Ce4+ contributes to the high antioxidation property of CeO2. Moreover, CeO2 nanoparticles can simulate CAT-like activity by producing H2O2 through its SOD-like activity, completing the redox cycle reactions to regenerate the initial oxidation state and regulate ROS levels [41]. Therefore, CAT-like nanozymes, such as CeO2, hold great potential for medical treatments targeting oxidative stress-related diseases.

GPx-like nanozymes

Glutathione peroxidase (GPx), a crucial selenoenzyme in the cellular antioxidant defense system, belongs to the protease superfamily [44]. It catalyzes the reduction of H2O2 to H2O using glutathione (GSH) as a cofactor. Some isoforms also reduce lipid peroxides to corresponding alcohols, protecting cells from oxidative damage. However, natural GPx suffers from intrinsic drawbacks, such as high cost, instability, and limited scalability. To overcome these limitations, researchers have developed nanozymes with GPx-like properties. These GPx-like nanozymes can be categorized into five groups based on the active center element: selenium-based, vanadium-based, manganese-based, copper-based, and others [36]. The main catalytic process of GPx-like nanozymes involves the reduction of H2O2 and organic hydroperoxides in the presence of reduced GSH. Similar to natural GPx, most GPx-like nanozymes follow a ping-pong mechanism [45], where hydroperoxide oxidizes their active sites to form peroxide intermediates. Among the studies on GPx-like nanozymes, only the self-assembled selenopeptide-anchored AuNP nanozyme demonstrated an ordered mechanism [46]. In 2014, Mugesh and co-workers firstly discovered V2O5 nanowires with GPx-like activity [47]. Their research demonstrated that V2O5 can protect cells from oxidative damage by catalyzing the degradation of various hydroperoxides (ROOH) using GSH as a reductant. Additionally, V2O5 nanowires scavenge H2O2 without interfering with natural antioxidant processes. They also prevent oxidative damage to cellular components such as lipids, proteins, and DNA, thereby playing a cytoprotective role. By restoring the redox balance, GPx-like nanozymes show great promise in inhibiting and combating oxidative stress, as well as treating diseases associated with ROS in bone-related diseases.

POD-like nanozymes

Peroxidase (POD), a natural enzyme widely distributed in a variety of organisms, usually catalyzes the conversion of substrates into oxidation products via the presence of H2O2 and organic peroxides. The majority of natural POD consist of ferric heme proteins that are able to catalyze H2O2 and generate intermediate species with high valence, capable of abstracting electrons from different substrates. In 2007, Gao et al. [1] reported that small-sized magnetic nanoparticles (Fe3O4 NPs) exhibited the intrinsic POD-like activity, whose mechanism and efficiency were similar to those of natural horseradish peroxidase. Since then, various nanomaterials based on noble metals such as Cu, Au, Ag, Pd, Ru, Rh, Pt, and Ir have been demonstrated to have POD-like activity [5]. The mechanisms of most POD-like nanozymes involve the decomposition of H2O2 into •OH and then the further oxidation of substrates. The tumor microenvironment is characterized by high H2O2 concentration and acidity. Capitalizing on this attribute, some POD-like nanozymes have emerged as alternative agents for in vivo and in vitro therapy, including antibacterial treatment or tumor therapy, leveraging the potent oxidative capacity of •OH. Furthermore, the POD-like activity can be photothermally amplified, thereby demonstrating the superior efficacy of metallic nanozyme-based photothermal therapy (PTT) and photodynamic therapy (PDT) synergistic approaches in cancer treatment [48, 49].

Nanozyme-conducted applications for specific orthopaedics diseases

Oxidative stress and inflammation, triggered by oxidative damage, are considered crucial factors in the incidence and progression of numerous orthopedic conditions. Numerous nanozymes have been discovered to be efficient in shielding cells from oxidative injury, thereby potentially preventing and treating various orthopedic diseases. Additionally, nanozymes possess the benefits of a stable structure, mutable activity, and diverse functions, endowing them with immense application potential in the management of ROS-associated orthopedic disorders (Table 1).

Table 1 The potential application of nanozymes in Orthopaedics

Nanozymes	Activity	Substrate	Diseases	Therapeutic mechanisms	Therapeutic effects	References	
HPBzymes	SOD, CAT	•OH, •OOH, H2O2	OA	↓Rac1/ROS/ NF-κB signaling	Protect chondrocytes; mitigate the inflammatory response; prevent chondrocyte ECM degradation.	[54]	
HMPBzyme	SOD, CAT	•OH, O2•−, H2O2	OA	↓HIF-1α; ↓ROS ↓TNF-α; ↓IL-1β; ↑Arg-1 and IL-10	Suppress inflammation; modulate the phenotypic conversion of macrophages; protect mitochondrial function; promote the anabolism of cartilage ECM.	[55]	
PPBzymes	CAT	•OH, H2O2	OA	↓JNK phosphorylation; ↓COX-2; ↓IL-6; ↑Col2a1; ↑aggrecan; ↑Sox-9	Promote cartilage generation; reduce cartilage degradation; reduce inflammation.	[56]	
Mn3O4@PDA@Pd-SS31	SOD, CAT	H2O2, O2•−, •OH	OA	↓MMP13; ↓1 L-1β; ↓IL-6; ↓TNF-α; ↑Col2a1; ↑ACAN	Targeted mitochondrial repair, cartilage protection, anti-inflammatory and antioxidant	[57]	
HA/PRP/BSA-MnO2	CAT, SOD	H2O2, O2•−, •OH	OA	↓ROS	ROS elimination; inflammation relief; cartilage repair promotion.	[58]	
Mn3O4@CS	SOD, CAT	H2O2, O2•−	OA	↓ROS; ↓iNOS; ↓COX-2; ↑Collagen II; ↑aggrecan	Protect against oxidative stress; protect cartilage against degeneration	[59]	
Pt/Co-SA-NSG	SOD, CAT	•OH, O2•−, •NO and H2O2	OA	↓ROS; ↓INOS; ↓TNF-α; ↓1 L-1β; ↓IL-6; ↓COX2; ↓NF-κB1; ↓MMP-13; ↓Bax; ↓Caspase-3; ↑Bcl-2; ↑CAT; ↑SOD1; ↑SOD2; ↑ATP; ↓Ca2+	Restore mitochondrial function; regulate ATP level; reduce inflammatory factors; increase antioxidant factors.	[140]	
Cu-N4ClG	SOD, CAT	O2•−, H2O2, •NO	OA	↓ROS; ↓RNS; ↓Bax; ↓Caspase-3; ↓Bcl-2; ↓MMP-13; ↓IL-6; ↑CAT; ↑SOD	Protect mitochondrial functions; protect chondrocytes; decrease inflammatory factors; elevate antioxidant factors.	[61]	
Pt SA/C3N4	SOD, CAT	O2•−, H2O2, •NO, •OH	OA	↓ROS/RNS; ↓TNF-α; ↓1 L-1β; ↓IL-6; ↓MMP13; ↑CAT; ↑SOD; ↑ATP; ↓Ca2+	Scavenge ROS/RNS; regulate mitochondrial respiratory chain complexes; reduce ROS/RNS; promote ATP production	[62]	
Pt-Se NP	SOD, CAT	H2O2, O2•−, •OH	OA	↓ROS; ↓iNOS; ↓MMP13; ↓MMP3; ↓TNF-α; ↓1 L-1β; ↓IL-6; ↑IL-10; ↑CD206; ↑M2 macrophage	Scavenge free radical; antioxidant; protect chondrocytes; protect mitochondrial function recovery; attenuate the progression of OA	[63]	
CuMHs	SOD, CAT	H2O2, O2•−, •OH	OA	↓ROS; ↓IL6; ↓MMP13; ↓MMP3; ↑Col2α1; ↑MMP; ↑Ca2+; ↑ATP	ROS scavenging; anti-inflammation; restore mitochondrial function.	[64]	
Cu MOF	SOD, CAT	H2O2, O2•−, •OH	OA	↓ROS; ↓iNOS; ↓HIF1α; ↑O2; ↓MMPs; ↑Col2α1; ↑M2 macrophage	Decrease intracellular ROS levels; relieve hypoxic microenvironment; modulate the polarization of macrophages; inhibit the degradation of cartilage matrix	[65]	
Mil-88a	SOD	•OH	OA	↓ROS; ↑Col2; ↓MMP13; ↓1 L-1β	Promote the expression of anabolism-related genes; inhibit the expression of catabolism-related genes.	[66]	
TP-Au@PCN	SOD, CAT	•OH, •OOH, H2O2	OA	↓ROS; ↑collagen II; ↑Sox9; ↑ aggrecan; ↑LC3B; ↑Parkin; ↓MMP13	Reduce oxidative stress; increase the autophagic flux; repair mitochondria; inhibit apoptosis.	[67]	
IONP	CAT	H2O2	OP	↓ROS; ↓Nox1; ↓Nox4; ↓SOD1; ↑Runx2	Antioxidant; regulate bone metabolism; bone targeting ability	[75]	
HPBZ	SOD, CAT	•OH, O2•−, H2O2	OP	↓ROS; ↓NF-κB; ↓MAPK; ↓PI3K/AKT signaling	Suppress osteoclast formation; inhibit bone resorption	[76]	
HPB@RC-ALN	CAT, SOD, GPx	H2O2, •OH, O2•−, NADPH	OP	↓ROS; ↓RANKL; ↓TRAP, CTSK and OSCAR; ↑OSX, RUNX2, OCN and ALP	Scavenge ROS; reduce oxidative stress; alleviate osteoblast senescence and

facilitate osteogenesis; suppress osteoclastogenesis

	[77]	
CeONP60/40	SOD, CAT	O2•−, H2O2, •OH	OP	↓ROS; ↑SOD1; ↑SOD2; ↑ALP, SP7, COL1 and OCN; ↑HIF-1α; ↓IL-6, IL-1β, RANKL, and CTSK	Prevent intracellular ROS accumulation, DNA damage, senescence, reduce pro-inflammatory and pro-osteoclastogenic markers.	[61]	
TiNTA-CeNPs	SOD, CAT	O2•−, H2O2	OP	↓ROS; ↑Runx2; ↑Col1; ↑Opn; ↑Ocn and Opg	Scavenge ROS; ameliorate osteogenesis	[79]	
Mg-ZIF	SOD, CAT	O2•−, H2O2	OP	↓ROS; ↑ELOVL2; ↑ FADS1; ↑ FADS2; ↑OPN, OCN, and RUNX2	Scavenge ROS; promote osteogenic differentiation; upregulate lipid metabolic pathways	[80]	
PBNPs	GPx, CAT, POD, SOD	H2O2, •OH, O2•−, NADPH	IVDD	↓extracellular ROS; ↑SOD1, SIRT1 and GPx4 in cytoplasm; activate Ras, p53, PI3K Akt, AMPK signaling ways; ↑SOD1, SOD2, SOD3; ↓MMP3/13 and Adamts5; ↑Aggrecan and Col1/2α1; ↑Pcna and ↓p53 in nucleus	Scavenge extracellular ROS; inhibit the ubiquitin-proteasome degradation of SOD 1 to eliminate intracellular ROS; activate the transcription of antioxidant enzymes.	[86]	
PBNPs@OBG	CAT	H2O2	IVDD	↓ROS; ↓MMP3	Antioxidant; reverse the

IVDD disordered microenvironment

	[87]	
Greigite nanozyme	CAT, SOD, GPx	H2O2, O2•−, •OH, NADPH	IVDD	↓ROS-p53‐p21 pathway	Antioxidant; improve the mitochondrial function; alleviate NPCs senescence	[88]	
MS@MCL	CAT	H2O2	IVDD	↓ROS; ↓IL-1β and TNF-α; ↓MMP3, MMP13 and ADAMATs-5; ↑Aggrecan and Col II	Down-regulate the local lactate level, reduce pro-inflammatory factors, protect cells from death, and enhance the synthesis of ECM, promote IVD regeneration	[89]	
NAC-CDs	SOD, CAT, GPx	O2•−, H2O2, •OH, GSH	IVDD	↓ROS; ↑Aggrecan and Col II; ↓IL-1β and TNF-α; ↓p21	Reduce ROS, maintain mitochondrial homeostasis, suppress cellular senescence, anti-inflammation	[90]	
CeONPs	SOD, CAT	O2•−, H2O2	Bone defect	↓iNOS; ↓IL-6; ↑CD163, IL-10, and TGF-β; Col-I, ↑OSX, OCN, Col I and BMP-7	Reduce acute and chronic inflammation; enhance MSC proliferation, osteogenic differentiation and mineralization	[94]	
CeO2-CS	CAT	H2O2	Bone defect	↓ROS	Suppress intracellular ROS generation and lipid peroxidation in osteoblast	[95]	
PTA/CeO2NZ	SOD, POD	O2•−, H2O2	Bone defect	↓ROS	Scavenge radicals; enhance preosteoblasts proliferation	[96]	
Pt@ZIF-8@La	SOD, CAT	•OH, H2O2, O2•−	Bone defect	↓ROS and NOS; ↓IL-1β and TNF-α; ↑ALP and OPG; ↑OCN and Col I	Anti-inflammatory; Promote osteogenesis	[97]	
CONPs	CAT, POD	H2O2,	SCI	↓ROS and iNOS; ↓Cox2, Nr-f2, P53, Casp3, IL‐1β, IL‐6, and TNF‐α	Reduce ROS, attenuate inflammation and apoptosis, and help locomotor functional recovery	[102]	
CeNZ-gel	CAT, SOD	H2O2, O2•−	SCI	↓ROS; ↑VEGF, Ang-1, and TGF-β1; ↑LC3-I and LC3-II; ↓p62	Regulate hostile microenvironment, promote spinal cord repair	[103]	
IRF-5SiRNA/M@pMn	SOD, CAT, GPx	O2•−, H2O2, GSH	SCI	↓ROS; ↓NF-κB signaling; ↓IL-1β and TNF-α; ↑TGF‐β and IL‐10	Anti-oxidative and anti‐inflammatory, remodel the extrinsic neural environment, facilitate nerve regeneration	[104]	
Co-SAzyme	SOD, CAT, GPx	H2O2, O2•−, •OH, •NO, ONOO−	SCI	↓RONS; ↓IL-1β, IL-6 and TNF-α	Eliminate RONS, anti-inflammatory, reduce microglial cells apoptosis, improve neural repairs	[105]	
USM[H]L	CAT	H2O2	Gout	↓UA and H2O2; ↓IL-1β, IL-6 and TNF-α; ↑IL-10; ↓NF‐κB signaling; ↑Akt signaling; ↑activating heat shock proteins; ↑M2 macrophage polarization	Decrease urate and inflammation, reprogram the inflammatory microenvironment; relieve joints welling and pain	[110]	
Pd-Ru/Uricase@RBC	CAT, POD	UA, H2O2	Gout	↓UA and H2O2	Degrade UA, decompose H2O2 to generate O2	[111]	
Co-doped MnO2	Uricase-like activity	UA, O2	Gout	↓UA	Oxidative decomposition of uric acid	[112]	
MVSM	Uricase-like activity, CAT	H2O2	Gout	↓UA and H2O2	Catalyze UA and decompose H2O2	[113]	
MVSM@MIP	Uricase-like activity	UA	Gout	↓UA	Catalyze UA	[114]	
ARP-PtNCs	Uricase-like activity, CAT, SOD, POD	UA, H2O2, O2•−	Gout	↓ROS, UA and H2O2	Degrade UA and scavenge ROS	[115]	
Pt/CeO2	Uricase-like activity, CAT, SOD	UA, DPPH, H2O2, O2•−	Gout	↓ROS and RNS, ↓UA and H2O2	Degrade UA, scavenge ROS, and eliminate RNS, alleviate pain and joint edema	[116]	
M@P-siRNAsT/I	CAT	H2O2	RA	↓ROS; ↑O2; ↓HIF-1α; ↓MMP3, MMP13 and VEGF; ↓IL-1β and IL-6	Anti-inflammation; alleviate hypoxia	[119]	
MMV-MnO2@DSP	SOD, CAT	O2•−, H2O2	RA	↓ROS; ↓NF-κB signaling; ↓IL-1β and TNF-α;	Neutralize oxidative stress correct macrophages fibroblast-like synoviocytes and chondrocytes; mitigate joint damage and cartilage injury	[120]	
ε-PLE@MnCoO/Gel	CAT, SOD	H2O2	RA	↓ROS; ↑O2; ↓HIF-1α signaling; ↓TNF-α, IL-1β, IL-6, PGE2, and NO; ↑ALP, BMP-2), RUNX-2, and OCN; ↓OPG, RANKL, and OPG/RANKL	Decompose ROS and generate O2; anti-oxidative and anti‐inflammatory promote osteogenic differentiation	[121]	
A-nanoceria	SOD, CAT, POD	O2•−, H2O2, NADH2	RA	↓ROS; ↓IL-1β and iNOS; ↑Arg-1; ↓M1/M2	Downregulate ROS; resolve hypoxia; inhibit inflammation; restore the misbalance of M1/M2 macrophages	[122]	
CeO2-ZIF-8@PDA	CAT, SOD	H2O2, O2•−, •OH	RA	↓ROS; ↓IL-6, IL-12β and iNOS; ↑O2; ↓HIF-1α signaling	Downregulate ROS; generate oxygen; inhibit inflammation	[123]	
HA@RH-CeOX	SOD, CAT	O2•−, H2O2	RA	↓ROS; ↓TNF-α, CD86, iNOS, IL-1β, and NF-κB; ↓Arg-1 and IL-10; ↑M1-to-M2 macrophage ratio	Decompose ROS; modulate the redox homeostasis; anti-inflammation; promote the M1-to-M2 macrophage repolarization	[124]	
Fe3O4-NS	POD	H2O2, •OH	OS	↑ROS; kill tumor cells; PTT/CDT	Generate ROS; inhibit tumor growth	[129]	
AKT-Fe3O4-CaO2	CAT, POD	H2O2, •OH	OS	↑•OH; ↓H2O2; ↑Ca2+ ions; magnetic hyperthermia; ↑BMP2, OCN, RUNX2, and COL1	Generate •OH; accelerate bone regeneration; suppress tumor growth	[130]	
FeSAC	CAT, POD	H2O2, •OH	OS	↑•OH; ↓H2O2; photonic hyperthermia; ↑COL1, BMP-2, OCN, and Runx2	Eradicated osteosarcoma cells, antibacterial and

anti-osteomyelitis

	[131]	
RhRu/Ti3C2Tx	CAT, POD	H2O2, •OH	OS	↑O2, •OH, and 1O2; ↓H2O2; CDT/PDT/PTT	Accelerate cell apoptosis or necrosis; inhibit tumor growth	[132]	
Ti–MnO2-CPA@Ce6	POD, glucose oxidase-like activity	•OH	Bone infection	↑•OH, ↑O2, ↓ glucose and H2O2 in the implant site environment, SDT antibacterial and immune-antibacterial,	Alleviate of immunosuppressive microenvironment, induction of bacterial immunogenic death and enhancement of bacterial-associated immunogen exposure; activating adaptive immunity	[136]	
Mn/HSAE@BCP	POD, OXD, CAT	H2O2, •OH	Bone infection	↑•OH and O2•−, ↑COL1, Runx2, OCN and OPG, CDT/SDT	Generate ROS to eradicate bacterial, enhance antibacterial activity and bone regeneration	[137]	
Cu-POM	POD	•OH	Bone infection	↑•OH; ↑intracellular copper; ↑M1- macrophage polarization; ↑TNF-α and IL-6; ↓IL-10; CDT/PTT	Inhibit the bacterial TCA cycle and energy availability. Promote intracellular perox-ide accumulation, bacterial cuproptosis-like death and biofilm disintegration	[138]	
FGO@MN	POD	•OH	Bone infection	↑ROS, ↑•OH; ↑intracellular iron; PTT	Impairs heat shock response in bacterial biofilms; trigger

iron overload; induces ferroptosis-like cell death; reactivate neutrophil function

	[139]	

Osteoarthritis (OA)

Osteoarthritis (OA) is a prevalent degenerative joint disease that causes pain and reduced mobility, significantly impacting quality of life [50]. The key pathological features of OA include articular cartilage degeneration and damage, reactive bone growth at the joint edges and subchondral points, and synovial inflammation. Although the exact mechanism of OA remains unclear, the role of ROS in its onset and progression has been well-established [51]. Excessive ROS production leads to imbalances in articular cartilage homeostasis, resulting in lipid peroxidation, protein carbonylation, and DNA damage. Additionally, elevated ROS levels promote the overexpression of inflammatory factors and overwhelm cellular antioxidant capacity, leading to chondrocyte death and exacerbation of joint cartilage damage [52, 53]. Consequently, researchers have increasingly focused on alleviating excessive ROS levels to restore oxidative stress balance and reduce the overexpression of inflammatory factors in OA using nanozymes. For instance, Hou et al. [54] synthesized a hollow Prussian blue nanozyme (HPBzyme) capable of remodeling the chondrocyte microenvironment to attenuate inflammation, cartilage extracellular matrix degradation, and cell apoptosis. This nanozyme protects articular cartilage and delays OA progression by inhibiting ROS and the Rac1/nuclear factor kappa-B (NF-κB) signaling pathway. Similarly, Xiong et al. [55] proposed a pH-responsive biodegradable hollow-structured manganese Prussian blue nanozyme (HMPBzyme) that synergistically inhibited oxidative damage and relieved hypoxia to suppress inflammation by promoting cartilage extracellular matrix anabolism, protecting mitochondrial function, and downregulating the expression of HIF-1α. It could also modulate macrophage phenotypic conversion from the pro-inflammatory M1 subtype to the anti-inflammatory M2 subtype for the treatment of OA. Also, Prussian blue nanozymes coated with Pluronic (PPBzymes) showed a high therapeutic efficacy owing to specifically inhibiting of c-Jun N-terminal kinase (JNK) phosphorylation to modulate inflammatory OA pathogenesis [56]. Li et al. [57] developed mitochondria targeting and NIR responsive Mn3O4@PDA@Pd-SS31 nanozymes, which could efficiently scavenge mitochondrial ROS, repair damaged mitochondrial function and promote cartilage regeneration. Furthermore, several studies have utilized hydrogels as carriers to synthesize multi-activity nanozymes, such as HA/PRP/BSA-MnO2 hydrogel [58] and Mn3O4@CS hydrogel [59], to decrease ROS levels in chondrocytes and inhibit cartilage degeneration during OA progression. Moreover, single-atom catalysts have been employed as carriers to enhance catalytic activity. For example, Zhao’s group engineered Pt/Co-SA-NSG [60], Cu-N4ClG [61] and Pt SA/C3N4 [62]single-atom nanozymes with high photothermal conversion performance, excellent SOD-like and CAT-like activity, and ROS scavenging ability. These nanozymes could restore mitochondrial function, regulate ATP levels, reduce inflammatory factor levels, and increase antioxidant factor levels, thereby alleviating OA progression. Wei et al. [63] also developed a hybrid Pt-Se nanozymes to scavenge ROS/RONS and regulate macrophage polarization to exert synergistic effects for OA therapy. In addition to metals and metal oxides, MOF have also shown promise as candidates for designing high-performance biomedical nanozymes due to their well-defined structures resembling proteins. A novel copper-morin-based MOF located morin hydrate (CuMHs) was employed as an ROS scavenger for OA therapy [64]. As shown in Fig. 1(A-C), CuMHs exhibited efficient antioxidant and anti-inflammatory functions, as well as the ability to repair mitochondrial function by increasing mitochondrial membrane potential, reducing calcium ion accumulation, and promoting ATP production. Following an 8-week intraarticular injection, the macroscopic image revealed that Cu6MH induced a notable regenerative effect on the cartilage layer and proteoglycan content (Fig. 1D). Yu et al. [65] also used a copper-based metal-organic framework (Cu MOF) as a comprehensive and powerful antioxidant nanozyme for OA treatment. Furthermore, a Mil-88a nanozyme co-loaded with an organic metal matrix (Mil-88a) [66] and a near-infrared-sensitive tea polyphenol-modified zirconium-based porphyrin metal-organic framework (TP-Au@PCN) [67] showed promising therapeutic strategies for OA. These advancements in nanozyme-based therapies provide potential solutions for reducing ROS levels and mitigating the progression of OA.

Fig. 1 Nanozymes for OA therapy. (A) Schematic illustration of the CuMHs by hydrothermal stirring and their in vivo therapy of OA rat model via modulating the microenvironment of articular cavity. •OH (B) and O2•− (C) scavenging capacity of morin hydrate and CuMHs by ESR. (D)Macroscopic observation of OA joints after intra-articular injection at 8 weeks. Reproduced with permission from Ref [64]. Copyright, 2023 Jinhong Cai et al

Osteoporosis (OP)

Osteoporosis (OP) is the most prevalent systemic bone disease in the elderly, characterized by an imbalance in bone metabolism and destruction of bone microstructure, resulting in increased skeletal fragility and susceptibility to fractures [68]. With the global aging population, the prevalence of OP has rapidly increased, making it a significant public health concern [69, 70]. The main cause of osteoporosis is generally attributed to an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. Numerous studies have shown that ROS play a crucial role in inducing osteoblast senescence and act as pivotal messengers in the signaling cascade of osteoclastogenesis [71, 72]. Additionally, the osteoporotic microenvironment is characterized by the infiltration of inflammatory factors and abnormal accumulation of ROS [73]. The inflammatory microenvironment and ROS accumulation jointly exacerbate the vicious coupling mechanism between osteoblasts and osteoclasts in the progression of osteoporosis [74]. Therefore, alleviating ROS is a key strategy to restore the balance between bone resorption and bone formation. Nanozymes, which can catalyze redox processes to regulate ROS levels, have great potential as therapeutic agents for OP. Among the various nanozymes, iron oxide nanoparticles (IONPs) have been extensively investigated and utilized in biomedicine due to their superior ROS scavenging ability [1]. Zheng et al. [75] designed and synthesized a novel bone-targeting IONP loaded with alendronate to treat ovariectomy-induced osteoporosis in mice. This composite nanomaterial exhibited excellent therapeutic activity because the iron oxide nanoparticles scavenge ROS to regulate bone metabolism, while alendronate endowed IONP with good bone targeting ability to revise OVX-induce bone loss. Similarly, Prussian blue has gained increasing attention in biomedicine as another iron-based nanozyme. As shown in Fig. 2(A-D), Ye et al. [76] used hollow Prussian blue (HPBZ) to normalize the OP microenvironment by inhibiting the nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Moreover, this multifunctional nanozyme exhibits ROS-scavenging capability, anti-inflammatory activity, anti-apoptotic ability thereby regulating osteoclast differentiation and delaying OP progression. Furthermore, Li et al. [77] synthesized a Prussian blue nanozyme loaded with the RANKL-CRISPR/Cas9 gene editing plasmid and modified with alendronate (HPB@RC-ALN) to modulate the osteoporotic microenvironment. This complex is capable of regulating genes and targeting bone, successfully correcting the abnormal metabolic status of the osteoporotic microenvironment. In addition to iron-based nanozymes, cerium-based nanozymes have also attracted significant attention due to their multi-enzyme-like activities and excellent antioxidant capacity. Among them, cerium oxide nanoparticles are the most commonly studied cerium-based nanozymes, as they easily undergo redox cycling by quick interconversion of the oxidation state between Ce4+ and Ce3+[40]. Wei et al. [78] employed an engineered artificial CeO2 nanozyme with a higher proportion of trivalent (Ce3+) surface sites to mitigate ionizing radiation-induced bone loss. Additionally, Shao et al. [79] used titania nanotube arrays as carriers to support CeNPs. Compared to single cerium oxide nanoparticles, CeNPs supported by titanium dioxide (TiNTA-CeNPs) can better preserve Ce3+ active sites, exhibiting more sustained superoxide dismutase activity to alleviate ROS and achieve the treatment of OP. Magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was also engineered to effectively scavenge ROS, regulates osteogenic and adipogenic to alleviate OP [80].

Fig. 2 Nanozymes for OP therapy. (A) Diagram of HPBZ-mediated normalization of disease microenvironment for treatment of OP. (B) HPBZ inhibit RANKL-induced osteoclastogenesis and bone resorption by inhibiting the NF-𝜅B, MAPK, and PI3K/AKT signaling pathways. (C) TRAP staining shows that HPBZ suppress the osteoclasts number and size depending on the dose. (D) Representative 3D micro-CT images of distal femur specimens. Reproduced with permission from Ref [76]. Copyright 2022, John Wiley and Sons

Intervertebral disc degeneration (IVDD)

Intervertebral disc degeneration (IVDD) is a degenerative spinal disease characterized by lower back pain and acute radicular pain in the lower extremities [81]. The main pathological features of IVDD include dehydrated nucleus pulposus, torn annulus fibrosus, and fissured cartilage endplate. Numerous studies have demonstrated that mechanical compression and inflammation are key factors in the development of IVDD, leading to a vicious cycle [82, 83]. As individuals age, the intervertebral disc gradually deteriorates. The closed environment of the intervertebral disc experiences an increase in ROS, which activate inflammatory pathways such as NF-𝜅𝛽 and MAPK/ERK [84, 85]. This results in cellular senescence and apoptosis of the nucleus pulposus cells (NPCs), while inhibiting cell proliferation. Additionally, the overproduction of ROS leads to increased oxidative stress and mitochondrial dysfunction, further exacerbating the progression of IVDD [84]. Therefore, finding solutions to effectively clear ROS is crucial for inhibiting inflammatory pathways and treating IVDD. Nanozymes, a promising type of catalytic nanomaterial, have the ability to scavenge ROS due to their excellent SOD-like and CAT-like activities. Prussian blue nanozyme, in particular, exhibits excellent biosafety and antioxidant properties, making it a promising candidate for IVDD therapy. As shown in Fig. 3(A-E), Zhou and colleagues demonstrated that Prussian blue nanoparticles (PBNPs) not only mitigate intracellular oxidative stress and enhance the intracellular activities of antioxidant enzymes, but also alleviate nucleus pulposus cellular degeneration by stabilizing SOD1 from ubiquitination-proteasome degradation [86]. However, Yang et al. [87] believed that systemic application of PBNPs was improper for IVDD treatment due to the avascular structure of the intervertebral disc. So they synthesized an injectable hydrogel incorporated with PBNPs for IVDD therapy. Another iron-based nanozyme, greigite nanozyme, has demonstrated promise in managing IVDD. For instance, Shi et al. [88] found that the greigite nanozyme exhibited exceptional SOD- and CAT-like activities and released substantial quantities of polysulfides. This capability facilitated the prevention of NPCs from senescence and reduced the inflammatory response. Moreover, manganese-based nanozymes, which share similar electron shell arrangements with iron-based nanozymes, have also been investigated for IVDD treatment. Shen et al. [89] synthesized an injectable microsphere incorporated with manganese dioxide nanozymes and lactate oxidase composite for inflammation relief and tissue regeneration in IVDD management. In addition to utilizing metals and metal oxides, organic nanozymes such as carbon dots have gained attention in biomedicine. Carbon dots, derived from natural plants, possess SOD, CAT, and GPx activities, allowing them to efficiently scavenge free radicals and GSH, thereby alleviating the process of senescence. Wu et al. [90] fabricated N-acetylcysteine-derived carbon dots (NAC-CDs) as a dual-functional antioxidant and anti-senescent agent to ameliorate IVDD, capitalizing on their potent enzyme-like activities.

Fig. 3 Nanozymes for IVDD therapy. (A) Molecular mechanism diagram of PBNPs alleviate oxidative stress in NPCs. (B) Illustration of the multiple enzyme-like activities of PBNPs, which are expected to scavenge the ROS in cells and alleviate the harsh oxidative stress microenvironment in degenerative disc disorders. (C) After H2O2 (0.6 × 10− 3%) stimulation and PBNPs (2 µg mL− 1), oxygen species in NP cells was detected via DCFH/DCF ROS detecting system. (D) Transmission electron microscope images of intracellular mitochondria in NPCs, after H2O2 (0.6 × 10− 3%) stimulation and PBNPs (2 µg mL− 1) treatment. Statistical chart shows IOD/area of red and green fluorescence. (E) Representative images of HE staining. Reproduced with permission from Ref [86]. Copyright 2022, Wiley-VCH GmbH

Bone defect

Bone defects, characterized by the loss of structural integrity in the bone, represent a prevalent clinical issue [91]. The primary causes of bone defects typically include high-energy trauma, tumors, infections, and so on. The treatment of bone defects remains a considerable challenge in orthopedics. Following bone injury, excessive ROS can cause severe inflammation, hindering bone regeneration and healing [92, 93]. Given that these two effects exacerbate each other, leading to an endless loop in bone remodeling, an accumulating body of evidence suggests that nanozymes, as a promising bone regeneration agents and ROS scavenger, not only alleviate oxidative stress impairment but also regulate osteoclastic differentiation and protect osteoblastic activities at the bone defect site [49]. Among these, cerium oxide nanozyme has been extensively used in the treatment of bone defects due to its outstanding antioxidant capacity. Wei et al. [94] synthesized multifunctional cerium oxide nanoparticles (CeONPs) that enhanced osteogenic differentiation and mineralization. In this study, CeONPs demonstrated SOD and CAT activities, which downregulated the expression of inflammatory factors and reduced oxidative stress. Furthermore, Li et al. [95] synthesized cerium oxide-incorporated calcium silicate (CeO2-CS) to protect osteoblastic cells from oxidative stress. The nanomaterial significantly reduced ROS production, improved MC3T3-E1 osteoblast viability, and demonstrated potential in the treatment of bone defects. Similarly, Yang et al. [96] designed multifunctional composite ceria nanozyme (PTA/CeO2NZ) by poly tannic acid coating on CeO2 nanoparticles surface. Compared to pure CeO2 nanoparticles, PTA/CeO2NZ exhibited stronger SOD activity and higher ROS scavenging capacity, thus maintaining the vitality of MC3T3-E1 osteoblastic cells. In addition, platinum (Pt) nanozymes with an outstanding ROS scavenging capability have also been utilized in the repair of bone defects. As shown in Fig. 4(A-E), Pan et al. fabricated a bimetallic Pt@ZIF-8@La nanozyme, which was synthesized through in situ encapsulation of Pt nanozymes by ZIF-8 [97]. This integration of multiactive elements achieves a synergistic therapeutic effect of immunomodulation and osteogenesis by upregulating the ratio of osteoprotegerin (OPG) / receptor activator of nuclear factor kappa-B ligand (RANKL).

Fig. 4 Nanozymes for bone defect therapy. (A) Synthesis flow chart and mechanism of action of Pt@ZIF-8@La: Diagram illustrating the promotion of bone tissue repair by Pt@ZIF-8@La through the regulation of osteoimmunology and osteogenic activity. (B) Semiquantitative analysis of ALP staining of MC3T3-E1 cells after osteogenic induction for 2 weeks. (C) Semiquantitative analysis of OPG/RANKL after Western blot. Quantitative analysis of BMD (D) and BT/TV (E) in ROI selection of Micro-CT 3D reconstruction of mouse calvaria. Reproduced with permission from Ref [97]. Copyright 2023, American Chemical Society

Spinal cord injury (SCI)

Spinal cord injury (SCI) is a severe traumatic injury that results in profound disability, characterized by permanent motor, sensory, and autonomic dysfunction [98]. It can be classified into primary and secondary injuries based on their underlying pathophysiology. The pathophysiological processes of SCI involve an initial primary injury phase, followed by a secondary injury phase, in which excessive production of ROS, particularly ROS, plays a critical role [99, 100]. The overproduction of ROS has been identified as a significant contributor to secondary injury, exacerbating acute damage in the injured spinal cord [101]. Therefore, strategies aimed at scavenging ROS and suppressing inflammation have emerged as effective approaches to mitigate secondary injury and promote SCI recovery. In recent years, researchers have made significant advancements in the field of nanozymes with antioxidant activity, which hold great potential for the efficient treatment of SCI by effectively scavenging toxic ROS. A notable nanozyme is cerium oxide nanoparticles, which display low toxicity and exhibit SOD-like activity, rendering them suitable for regulating the microenvironment of SCI. Kim et al. conducted a study in which they injected cerium oxide nanoparticles into the contusion-injured spinal cords of rats. As depicted in Fig. 5 (A), the administration of CONPs has been observed to mitigate the accumulation of ROS, suppress inflammation and apoptosis, and thereby facilitate the recovery of locomotor functions in individuals experiencing acute SCI [102]. In another work, Xu et al. [103] devised a pioneering strategy that involved the combination of ceria nanoparticles with mesenchymal stem cells encapsulated within a hydrogel, resulting in highly efficient spinal cord repair. Their research unequivocally demonstrated that the stress-alleviating properties of cerium oxide nanoparticles, when coupled with the paracrine effects of mesenchymal stem cells, significantly expedite angiogenesis, nerve regeneration, and motor function restoration in the aftermath of SCI. Furthermore, researchers have also explored the use of gene-edited tools in combination with nanozymes for the treatment of SCI. Xiong et al. [104] fabricated a novel “nanoflower” Mn3O4 composite incorporating “pollen” IRF-5SiRNA, which served as a comprehensive antioxidant and anti-inflammatory therapy for SCI. In this research, Mn3O4 nanozymes potently catalyzed ROS to produce O2, aiding in reducing oxidative stress and fostering angiogenesis (Fig. 5B-C). Concurrently, the IRF-5SiRNA was capable of ameliorating the inflammatory phenotype by diminishing the expression of interferon regulatory factors-5 (IRF-5). Therefore, it could accelerate neuronal formation and enhanced long-term motor function recovery in SCI rats (Fig. 5D). In addition, single-atom nanozymes have gained significant attention in antioxidative therapies due to their excellent catalytic efficiency and complete utilization of metal atoms compared to other nanozymes. Jiang et al. [105] synthesized a commercially available single-atom cobalt nanozyme to mitigate RONS and inflammation in the secondary injury of SCI. Furthermore, this nanozyme effectively diminished the apoptosis and pro-inflammatory cytokine levels of microglial cells, prompting functional recovery and neural repairs in the SCI-rat model.

Fig. 5 Nanozymes for SCI therapy. (A) Schematic illustration of CONPs in secondary injury after spinal cord contusion treatment. Reproduced with permission from Ref [102]. Copyright 2017, John Wiley and Sons. EPR for the elimination of B) •OH and C) O2•−. (D) Examination of hind limb motor function recovery in rats using typical footprints (forepaw, blue ink; hind paw, red ink.) Reproduced with permission from Ref [104]. Copyright 2023, John Wiley and Sons

Gout

Gout is a common inflammatory arthritis caused by the buildup of uric acid crystals in the body [106]. It typically presents as acute pain in one or more joints, but in severe cases, it can lead to permanent joint damage and disability. Hyperuricemia, characterized by high levels of uric acid (UA) in the blood, is considered a prerequisite for the formation of monosodium urate (MSU) crystals and one of the most important etiologies of gout [107]. The current treatment for gout involves managing pain and inflammation during a gout flare using medications such as corticosteroids, non-steroidal anti-inflammatory drugs, IL-1 inhibitors, and colchicine [108]. Long-term therapy also includes medications that lower uric acid levels, such as uricase agents and non-enzyme medications. Uricase-based therapeutics have gained widespread recognition as an efficacious treatment modality for gout, attributed to their notable catalytic properties [109]. However, the accumulation of H2O2, a byproduct of uricase-mediated oxidation of uric acid to allantoin, may lead to deleterious side effects, particularly within the confines of a closed joint environment. This results in oxidative stress within cells and contributes to the pathogenesis of chronic joint damage. Recent investigations have centered on the employment of uricase in conjunction with CAT or CAT-like nanozymes within a cascade reaction system, sequentially dismantling uric acid and H2O2 to mitigate H2O2 accumulation. For example, Chen et al. [110] synthesized uricase and Fe3O4 nanozyme camouflaged macrophage-erythrocyte hybrid membrane liposomes to treat gout in rats. Similarly, Ming et al. [111] developed a novel nanoreactor consisting of uricase and Pd/Ru nanozymes coated with red blood cell membranes (Pd-Ru/Uricase@RBC) for the treatment of hyperuricemia. These uricase and nanozymes with CAT-like activity can decompose UA and H2O2, respectively, and produce oxygen as a final product. The decomposition of UA is an oxygen-consuming process, leading to a beneficial cycle. Cell-membrane-coated nanoreactors have the advantage of long circulation and intracellular retention times due to their immune escape and lysosomal escape properties. In addition to natural uricase, various nanomaterials with good stability under extreme conditions exhibit uricase-like activity. Parmekar et al. [112] synthesized cobalt-doped MnO2 nanozymes for the degradation of UA and the potential treatment of painful gouty arthritis. Furthermore, Liu et al. [113] used mixed valence state metal-organic frameworks with cerium to effectively catalyze UA in human urine, paving the way for the treatment of UA-related diseases. Moreover, MVSM@MIP with high selectivity and affinity that can also catalyze UA to treat gout and hyperuricemia [114]. When a single nanozyme possesses both uricase-like activity and catalase-like activity, it functions as a self-cascade nanoreactor for the treatment of hyperuricemia and gout. Liu et al. [115] synthesized arginine-rich peptide-Pt nanoparticle cluster (ARP-PtNC) nanozymes that mimic the typical enzymatic cascade systems of uricase/catalase for the treatment of gout. Lin et al. [116] also synthesized a single nanozyme composed of Pt/CeO2 with the activity of degrading UA and eliminating H2O2 simultaneously for alleviating pain in acute gout rats (Fig. 6A-C). These nanozymes act as a self-cascade system that mimic enzymatic cascade systems of uricase/catalase have gained increasing attention for the treatment of hyperuricemia and gout.

Fig. 6 Nanozymes for gout therapy. (A) Schematic illustration of the design and synthesis of the Pt/CeO2 nanozyme based on platinum-group metals and self-cascade uric acid degradation for acute gout therapy. (B) Differences in weight distribution between bilateral hind limbs of rats at 6 and 24 h. (C) Quantification of stride length, step length, and the length of front/rear paw prints at 6 h. Reproduced with permission from Ref [116]. Copyright 2021, American Chemical Society

Rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the immune system attacking the joints’ lining, resulting in chronic inflammation [117]. Early RA is associated with various pathophysiological changes, such as synovial hyperplasia, pannus formation, inflammatory cell infiltration, and local hypoxia [118]. Among these mechanisms, the inflammatory response and oxygen depletion play crucial roles in the development and progression of RA [106]. Therefore, the treatment of RA focuses on alleviating inflammation and ameliorating hypoxia. Nanozyme, which possess the ability to scavenge ROS, alleviate hypoxia, and exhibit anti-inflammatory activity, hold great promise as a novel approach for the treatment of RA. It offers new insights into managing RA and have the potential to overcome the limitations of current therapeutic options such as nonsteroidal anti-inflammatory drugs and glucocorticoids. Recently, Chen et al. [119] showed that encapsulation of both Prussian blue nanozymes and tumor necrosis factor-α/interleukin-6 silenced small interfering RNAs within biomimetic macrophage membrane vesicles (M@P-siRNAsT/I) that can downregulate the expression of inflammatory factors TNF-α/IL-6 and alleviate hypoxia in the RA microenvironment. Similarly, Jia et al. [120] also synthesized manganese dioxide nanozymes coated with macrophage microvesicles and dexamethasone sodium phosphate (MMV-MnO2@DSP). In their study, the manganese dioxide nanozymes can restore the metabolism of O2•− and H2O2, while macrophage microvesicles help manganese dioxide nanozymes circulate in the blood and reach the site of inflammation and dexamethasone sodium phosphate block the feedback loops of TNF-α and IL-1β. In another study, a nanozyme-reinforced hydrogel with BMSCs was used to reshape the hostile RA microenvironment and improve prosthetic interface osseointegration [121]. The synthesized hydrogel system exhibits the ability to efficiently decompose endogenous H2O2, yielding O2, and mitigates the hypoxic and oxidative microenvironment of rheumatoid arthritis (RA). This effectively creates an optimal 3D microenvironment for bone marrow stromal cells (BMSC) proliferation and osteogenesis. Apart from Prussian blue and manganese-based nanozymes, ceria-based nanozymes have also been widely used in the treatment of RA due to their ability to scavenge free radicals. For instance, Kalashnikova et al. [122] synthesized albumin-cerium oxide nanoparticles using the biomineralization process. These small nanoparticles displayed excellent ROS scavenging activity through SOD-like and CAT-like activity, and converted pro-inflammatory macrophage phenotype into an anti-inflammatory phenotype in a collagen-induced arthritis mouse model. Furthermore, Chen et al. [123] synthesized polydopamine-coated CeO2-doped zeolitic imidazolate framework-8 nanocomposite, which could treat RA through NIR-photothermal/ROS-scavenging/oxygen-enriched combinative therapy and down-regulate inflammatory factors and HIF-1α. In addition, a ceria oxide nanozyme-incorporated Rhein-loaded biopolymer-based micelle formulation (HA@RH-CeOX) has been developed for the treatment of RA [124]. As depicted in Fig. 7 (A-D), the HA@RH-CeOX micelles possess the capacity to eliminate cellular ROS through enzymatic-like catalytic activity, suppress TLR4-mediated immune signaling via RH-dependent NF-κB inactivation, and reprogram M1 macrophages to the M2 phenotype, ultimately restoring normal articular structure and function.

Fig. 7 Nanozymes for RA therapy. (A) Construction of the ceria oxide nanozyme-complexed biopolymer-based micelles and their redox homeostasis normalization effects on M1 macrophages in RA microenvironment. (B) Thermographic images of left hind paw of collagen-induced arthritis mouse models after different treatment showing the localized temperature changes as an indicator of the inflammation status. Quantitative analysis results of (C) paw temperature and (D) paw swelling states at various time points after treatment with RH, HA@RH, and HA@RH-CeOX. Reproduced with permission from Ref [124].Copyright 2023, American Chemical Society

Osteosarcoma (OS)

Osteosarcoma (OS), the most common malignant bone tumor originating from osteogenic cells, predominantly affects children and adolescents [125]. The standard treatment for OS involves a combination of surgical excision and chemotherapy. Despite the significant improvement in patient outcomes resulting from this therapeutic approach, the survival rate for OS has remained stagnant over the past four decades [126, 127]. Moreover, the administration of high doses of chemotherapy drugs inevitably leads to severe side effects, including myelosuppression, vomiting, nausea, and hair loss [128]. Therefore, there is an urgent need to develop therapeutic strategies that can enhance treatment efficacy while minimizing adverse reactions. Nanozymes, a promising field in malignancy therapy, have recently garnered considerable attention due to their superior catalytic ability to modulate ROS in the tumor microenvironment. For instance, Du et al. [129] synthesized ferric oxide nanosheet-engineered Mg alloy (Fe3O4-NS) for synergetic osteosarcoma photothermal/chemodynamic therapy (PTT/CDT). The alloy implant exhibited significant antitumor properties in vivo and in vitro, owing to the excellent nanocatalytic ability and high photothermal conversion efficiency of Fe3O4. Similarly, Dong et al. [130] fabricated a three-dimensional printed akermanite scaffold impregnated with calcium peroxide and iron oxide (AKT-Fe3O4-CaO2) for the treatment of OS. In this scaffold, the loaded CaO2 nanoparticles produced sufficient H2O2 in the acidic tumor microenvironment, and the co-loaded Fe3O4 nanozymes could catalyze pregenerated H2O2 into •OH via Fenton-like catalytic reaction. Especially, magnetic Fe3O4 NPs would be heated by exogenous alternative magnetic field irradiation, and the local temperature elevation promoted the generation of •OH in turn, achieving a synergistic effect of OS. Importantly, the loaded CaO2 NPs released extra Ca2+ ions to enhance bone regeneration. Moreover, Wang et al. [131] described a “scaffold engineering” strategy that integrates highly active single-atomic iron catalysts (FeSAC) into a 3D printed bioactive glass scaffold, which provided desirable osteosarcoma-therapeutic functionalities in conjunction with concurrent antitumor, antibacterial, and tissue-regeneration effects. In addition to iron-based nanozymes, noble metal nanozymes present potential applications for the treatment of OS. As illustrated in Fig. 8, Liang’s group fabricated 2D titanium carbide-supported RhRu alloy nanoclusters (RhRu/Ti3C2Tx), which exhibited notable CAT and POD-like activities [132]. Moreover, the RhRu/ Ti3C2Tx was employed for synergistic interventions combining chemodynamic therapy, photodynamic therapy, and photothermal therapy in the treatment of OS. Apart from the iron-based nanozyme, noble metal nanozymes hold the promise for the treatment of OS.

Fig. 8 Nanozymes for OS therapy. Scheme of the potential mechanism of RhRu/Ti3C2Tx nanozymes synergistic treatment of OS. Reproduced with permission from Ref [132].Copyright 2023, John Wiley and Sons

Bone infection

Bone infections represent a group of musculoskeletal diseases caused by microbial seeding through blood-borne or exogenous pathways [133]. These include graft-associated osteomyelitis, fracture-associated infection, acute blood-borne osteomyelitis, and infectious bone defects [134]. Although various treatment approaches, such as bone transplantation, bone transport technology, bone-induced membrane technology, and antibiotic-composite slow-release carrier implantation, are widely employed in the clinical management of bone infections, persistent challenges remain, including prolonged treatment durations, antibiotic resistance, and complications in donor areas [135]. Consequently, there is an urgent need to explore novel antibacterial strategies to address these issues. Recently, nanozyme-based antibacterial therapy has emerged as a promising therapeutic approach with significant clinical potential, exhibiting broad-spectrum antibacterial activity. Nanozymes can catalytically generate highly toxic ROS that disrupt bacterial membranes and induce bacterial apoptosis. For instance, Xu et al. [136] developed a multifunctional coating on titanium implants, consisting of manganese dioxide nanosheets with cascade catalytic enzyme activity and a responsive degradable hydrogel (Ti–MnO2-CPA@Ce6). This approach effectively eliminated bacteria in an established diabetic implant-associated infection model and activated systemic antibacterial immunity, providing long-term antibacterial protection (Fig. 9). Furthermore, Gao et al. [137] reported the rational integration of manganese single-atom nanozymes into 3D-printed bioceramic scaffolds (Mn/HSAE@BCP scaffolds), which exhibited excellent multienzyme-like activities to generate ROS for enhanced antibacterial activity and bone regeneration. For bacterial biofilm-associated infections, Mei et al. [138] proposed a strategy involving a biofilm microenvironment responsive copper-doped polyoxometalate cluster (Cu-POM) combined with mild photothermal therapy and macrophage immune re-stimulation to eradicate bacterial biofilms. Additionally, Zhu et al. [139] developed a novel antibiofilm approach using an iron-actuated Janus ion therapy based on a photothermal nanozyme microneedle patch (FGO@MN) for effective antibiofilm activity and immune reactivation. In conclusion, nanozymes provide a promising approach for the treatment of clinical bone infections.

Fig. 9 Nanozymes for bone infection therapy. (A) Schematic illustration of the construction of Ti-MnO2-CPA@Ce6 substrate. (B) The therapeutic mechanism of Ti-MnO2-CPA@Ce6 substrate-mediated SDT-catalytic therapy to efficiently kill S. aureus and activate adaptive immune for persistent against infection. Reproduced with permission from Ref [136]. Copyright 2024, Elsevier Ltd

Conclusion and Outlook

Since the identification of peroxidase-like iron oxide nanozymes, a multitude of nanomaterials with intrinsic enzyme-like activities have been recognized. Presently, it has been established that nanozymes exhibit a wide array of enzymatic activities, including SOD, CAT, GPx, POD, and OXD. Among them, SOD, CAT, and GPx-like nanozymes have garnered considerable attention in the context of certain bone disorders, attributable to their capacity to scavenge free radicals. Furthermore, POD-like nanozymes are instrumental in catalyzing the overproduction of H2O2 in the tumor microenvironment, thereby generating a large quantity of toxic ROS that can induce cell apoptosis and inhibit tumor growth. Consequently, numerous studies have corroborated the potential of nanozymes as nanomedicine for orthopedic disease therapy. This review provides a succinct overview of the classification and catalytic mechanisms of nanozymes, and encapsulates the progress made in nanozyme research for orthopedic disorders, primarily through ROS moderation.

Recent preliminary findings indicate the potential of nanozymes in the therapy of orthopedic diseases, particularly in ROS-related regulatory interventions, which may significantly influence clinical practice. Nevertheless, the field remains in its infancy, facing several fundamental and technical challenges that require resolution.

To design nanozymes with pharmacological activity, a comprehensive understanding of their catalytic mechanisms and structure-activity relationships are essential, serving as a prerequisite for advancing their biomedical applications. Currently, research in the field of nanozymes primarily focuses on enhancing their catalytic activity. However, the relationship between catalytic activity and pharmacological action may not be linear. Additionally, the structural characteristics of nanozymes-such as size, morphology, composition, and surface properties-can induce supplementary biological effects beyond catalysis, potentially influencing therapeutic outcomes. Therefore, future studies should prioritize establishing a direct correlation between the structure of nanozymes and their therapeutic efficacy, rather than solely emphasizing catalytic activity.

Notably, the biomedical applications of nanozymes are expanding beyond ROS regulation. For instance, certain nanozymes exhibit uricase-like, acetylcholinesterase-like, and phosphatase-like activities. Thus, nanozymes also show promise for the treatment of metabolic disorders through the regulation of substance metabolism.

From a translational perspective, it is crucial to address several key issues, including biosafety, biocompatibility, immunogenicity, and pharmacokinetic parameters. As inorganic nanomedicines, the behavior of nanozymes within the human body remains largely unpredictable. Consequently, it is imperative to focus on metabolism and safety concerns in vivo. Future efforts should integrate the technologies and mechanisms of pharmaceutics and pharmacology to systematically enhance the performance and therapeutic effects of nanozymes.

Author contributions

X.G . wrote the manuscript, J.Z. checked different sections of the manuscript. Y.G. and L.Y. edited the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82260181), Key project of Natural Science Basic Research Plan of Shaanxi Province (2022JZ-43) and the National Key Research and Development Program of China (No. 2022YFC2407503).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study doesn’t contain any animal and human experiments.

Consent for publication

All authors agreed to publish this manuscript.

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.
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