Nanozyme-Mediated Joint Homeostasis Restoration: Emerging Strategies for Arthritis Therapy

Introduction

Rapid advancements in nanomedicine have introduced novel strategies to overcome traditional biomedical limitations.¹ Nanozymes—nanomaterials with intrinsic enzyme-like catalytic activity—have emerged as a significant therapeutic focus, integrating nanoscale physicochemical properties with high catalytic efficiency.^2,3 Compared to natural enzymes, nanozymes circumvent conformational instability, high production costs, and complex functionalization, offering superior structural stability, industrial scalability, and tunable catalytic activity.⁴ Crucially, by mimicking antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione peroxidase (GPx), nanozymes effectively remodel pathological microenvironments via reactive oxygen/nitrogen species (ROS/RNS)⁵ scavenging and immune homeostasis regulation.^6,7 This microenvironmental modulation directly addresses the oxidative stress and inflammatory cascades central to the pathogenesis of rheumatoid arthritis (RA), osteoarthritis (OA), and gouty arthritis (GA).^8–10 Consequently, the introduction of nanozyme technology into arthritis therapeutics offers new possibilities for advancing therapeutic approaches.^11,12

Exacerbated by aging populations and shifting lifestyles, the rising global incidence of RA, OA, and GA constitutes a major public health burden.^13,14 Current clinical management primarily relies on pharmacotherapies, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying antirheumatic drugs (DMARDs), and targeted biologics such as tumor necrosis factor-α (TNF-α) inhibitors.^15,16 These interventions effectively manage symptoms: NSAIDs and GCs rapidly suppress acute inflammation,¹⁷ whereas biologics significantly slow disease progression.¹⁸ However, current clinical treatments still face significant limitations. Long-term systemic NSAID and GC use induces adverse effects, including gastrointestinal ulcers, cardiovascular risks, and osteoporosis.¹⁷ Widespread application of targeted biologics is restricted by high costs, immunogenicity, and secondary infection risks.¹⁸ Furthermore, these therapies primarily provide symptomatic relief or single-pathway blockade rather than reversing the damaged joint microenvironment. Similarly, the complexity of the intra-articular environment is one of the major factors contributing to the poor bioavailability and suboptimal targeting efficacy of conventional small-molecule drugs in clinical applications.^19,20 To address these challenges, nanozymes offer a compelling alternative, providing multi-target microenvironment remodeling, sustained antioxidant catalysis, and programmable targeted delivery.

However, a profound translational gap separates laboratory nanocatalysis from clinical joint disease modification, whereas existing reviews predominantly adopt a chemistry-oriented classification based on material synthesis methodologies, focusing on aspects such as catalytic mechanisms, activity regulation, and fields of development and application.^4,6 In contrast, this review advocates for a return to a function-first paradigm in nanozyme development. We systematically summarize and discuss the various strategies for alleviating the pathological microenvironment of arthritis over the past five years (Scheme 1). By correlating atomic-level active site engineering of nanozymes with the distinct pathophysiological features of RA, OA and GA, we propose a framework with a unique perspective from translational medicine. Following this, We detail nanozyme design strategies, focusing on therapeutic applications and mechanisms for joint microenvironment remodeling. Finally, we assess translational obstacles, with a particular focus on long-term biosafety and in vivo metabolism, and outline future research directions. We hope this review serves as a robust theoretical framework, inspiring innovative approaches for the design of safer, smarter, and more efficient nanomedicines for arthritis management.

Scheme 1 Nanozyme-base strategies for arthritis treatment.

Pathological Characteristics and Conventional Therapy

Core Pathological Mechanisms

Joint inflammation results from multifactorial disruptions to tissue homeostasis, driving progressive degeneration. Despite differing etiologies, RA, OA, and GA share five pathological hallmarks: oxidative stress, cytokine dysregulation, immune cell imbalance, synovial hyperplasia, and cartilage degeneration (Figure 1).

Figure 1 Common pathological features of arthritis.

Oxidative Stress and ROS Accumulation

While physiological ROS are essential signaling molecules for cellular homeostasis, the articular microenvironment disrupts this balance via a vicious hypoxia-inflammation cycle. Hypoxia-induced ROS generation and hypoxia-inducible factor 1 subunit α (HIF-1α) upregulation overwhelm endogenous antioxidants (eg, SOD, CAT), precipitating profound oxidative stress.²¹ Consequently, excessive ROS inflict direct macromolecular oxidative damage and act as second messengers to activate the nuclear factor-κB (NF-κB) pathway, driving a pro-inflammatory/pro-oxidative feedback loop.²² Despite varying origins, ROS-mediated pathological consequences converge across arthritis subtypes. In RA, immune cell respiratory bursts and sustained ROS release by fibroblast-like synoviocytes (FLS) synergistically amplify TNF-α expression.^23,24 Mechanical overload and aging induce mitochondrial ROS accumulation, activating the HIF-α/Matrix Metalloproteinase(MMP) 13 axis to drive chondrocyte catabolism and joint degradation.^25,26 Furthermore, in GA, ROS generated during immune cell phagocytosis of urate crystals serve as the essential trigger for NLRP3 inflammasome activation, fundamentally driving crystal-induced acute joint inflammation.^27,28

Uncontrolled Release of Pro-Inflammatory Cytokines

In arthritis, dysregulated pro-inflammatory cytokines orchestrate molecular networks driving progressive joint destruction.²⁹ Elevated synovial expression of TNF-α, IL-1β, IL-6, and IL-17 synergistically promotes immune infiltration, angiogenesis, and extensive matrix degradation, fundamentally destabilizing the articular environment.^30,31 Distinct cytokine profiles dictate disease-specific manifestations: RA features a TNF-α and IL-6-dominated “cytokine storm” directly driving pannus formation;³² OA presents as DAMP-induced low-grade chronic inflammation, suppressing cartilage synthesis and sensitizing pain pathways; whereas GA relies on an IL-1β-centric cascade to trigger acute inflammation.^33,34 Despite these divergent modalities, all arthritic forms ultimately perpetuate irreversible joint destruction by establishing self-sustaining inflammatory microenvironments that chronically elevate pro-inflammatory signaling and abrogate tissue repair mechanisms.³⁵

Macrophage Polarization Imbalance

Macrophage phenotypic plasticity fundamentally regulates joint inflammation, and the polarization disequilibrium between M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes underpins arthritis chronicity and tissue repair failure.³⁶ Driven by the sustained activation of pathways such as Granulocyte-macrophage colony-stimulating factor (GM-CSF) and Toll-like receptor 4 (TLR4)/Myeloid differentiation factor (MyD88)/NF-κB, M1 macrophages release copious pro-inflammatory mediators and propagate bone destruction,³⁷ whereas the reparative functions of the M2 phenotype are concurrently suppressed.³⁸ Targeting these signaling cascades is thus necessary to reverse pathogenic macrophage polarization. While M1-driven inflammation consistently fuels joint pathology, specific manifestations vary: in RA, M1 macrophages primarily drive persistent bone erosion;³⁹ in OA, M1-secreted factors induce osteophyte formation;⁴⁰ and in GA, “frustrated phagocytosis” of urate crystals forms chronic granulomas (tophi).⁴¹ Therefore, targeted macrophage repolarization represents a pivotal strategy for chronic arthritis management.

Synovial Hyperplasia and Pannus Formation

Synovial hyperplasia and invasive pannus formation link articular inflammation to structural destruction. Chronic inflammation confers tumor-like anti-apoptotic and invasive phenotypes upon FLS. Alongside hypoxia-induced neovascularization, these transformed cells form a protease-rich “synovium-vascular” axis that actively degrades cartilage and bone.^42,43 While driven by this common axis, disease-specific manifestations vary: RA is characterized by highly invasive pannus; OA presents with synovitis and fibrosis secondary to cartilage loss; and chronic GA features granulomatous synovitis surrounding tophi, causing distinct “punched-out” bone defects.^44,45

Chondrocyte Apoptosis and ECM Degradation

Chondrocyte apoptosis and extracellular matrix (ECM) degradation constitute the terminal pathway of irreversible joint dysfunction.²⁶ Driven by the pro-inflammatory microenvironment, significantly upregulated proteases, specifically MMP-1/13 and ADAMTS-4/5, catalyze the irreversible hydrolysis of type II collagen and aggrecan, making their inhibition critical for preserving articular structural integrity.^29,46 While distinct pathologies trigger chondrocyte death via unique mechanisms: mitochondrial-mediated senescence and apoptosis in OA;^47,48 Fas/FasL death receptor activation in RA;^49,50 and MSU crystal-induced, NLRP3/IL-1β-driven MMP release in GA,⁵¹ they universally converge on these destructive ECM-degrading programs. Targeting this shared convergence point consequently offers profound broad-spectrum therapeutic potential. Because pro-inflammatory cytokine-driven chondrocyte death and ECM degradation remain the universal drivers of structural damage, specifically inhibiting terminal enzymes like MMP-13 and ADAMTS-5 can effectively arrest progressive joint destruction across arthritic conditions.

Developments and Challenges of Current Therapies

Current clinical paradigms for RA, OA, and GA primarily rely on the stepwise administration of GCs, NSAIDs, DMARDs, and biological agents.⁵² However, the necessity for high-dose systemic administration to overcome low intra-articular bioavailability inevitably precipitates systemic toxicity while failing to effectively neutralize the localized reactive oxygen species sustaining chronic inflammation. Prolonged glucocorticoid exposure induces metabolic disturbances and accelerates cartilage degradation, whereas NSAIDs carry concurrent gastrointestinal and cardiovascular risks alongside disruptions to chondrocyte metabolism.^53,54 The therapeutic efficacy of conventional DMARDs is frequently constrained by hepatotoxicity and gastrointestinal intolerance.⁵⁵ Despite biologics improving RA outcomes, nearly 40% of patients develop secondary resistance due to anti-drug antibodies, and the clinical utility of convenient oral JAK inhibitors (eg, tofacitinib, baricitinib, upadacitinib) remains restricted by elevated risks of thrombosis and malignancy.^56,57 Disease-specific challenges further undermine therapeutic efficacy beyond systemic toxicity: standard regimens for refractory RA struggle to address central sensitization and synovial fibrosis;⁵⁸ OA treatment is relegated to palliative management or joint replacement absent approved disease-modifying agents;⁵⁹ and gout management is complicated by poor patient adherence to urate-lowering therapies alongside allergic reactions triggered by highly immunogenic drugs.^60,61 Collectively, existing standard therapies prove inadequate in dismantling the central hypoxia-ROS-inflammation axis within the articular microenvironment, rendering them incapable of arresting the vicious cycle of joint destruction.

Multidimensional explorations at the research frontier attempt to circumvent these clinical bottlenecks, although such emerging strategies present distinct translational barriers. At the molecular intervention level, small-molecule antioxidants and natural polyphenols, including resveratrol, curcumin and quercetin, function by scavenging free radicals or activating the Nrf2 pathway. Specifically, resveratrol upregulates SOD to suppress NF-κB activation, while quercetin mitigates chondrocyte endoplasmic reticulum stress via the SIRT1/AMPK axis.⁶² However, poor aqueous solubility, weak chemical stability, and marginal intra-articular bioavailability severely compromise their in vivo therapeutic efficacy relative to in vitro performance.⁶³ Exogenous natural antioxidant enzymes (SOD, CAT, GPx), theoretically represent highly efficient and specific interventions, yet they remain susceptible to rapid lymphatic clearance and proteolytic inactivation driven by the mildly acidic microenvironment and elevated MMP concentrations within the inflamed joint cavity.⁶⁴ While specific biologics and small-molecule inhibitors achieve precise blockade of inflammatory signaling but frequently elicit resistance through compensatory pathway activation, concurrently increasing the risk of systemic immunosuppression during long-term administration.⁶⁵ Advanced genetic tools like CRISPR-Cas9 gene editing offers precise transcriptional silencing of pro-inflammatory genes. Nevertheless, off-target effects and Cas9 protein immunogenicity remain primary obstacles to clinical translation.^66,67 Within biologics and regenerative medicine, mesenchymal stem cells (MSCs) and their exosomes exhibit unique advantages in inducing M2 macrophage polarization and promoting cartilage regeneration, yet localized oxidative stress and acidic conditions drastically restrict the survival and functional durability of transplanted cells.⁶⁸ Similarly, recently highlighted 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors, which promote endogenous cartilage regeneration by protecting PGE2, demonstrate encouraging outcomes in animal models. But their human safety profiles, articular targeting efficiency, and impact on systemic immunity require robust clinical validation.⁶⁹ Beyond joint disorders, nanomaterial platforms have been actively investigated in related musculoskeletal conditions, such as lubricious nanofibers for tendon adhesion prevention and gradient scaffolds for tendon-bone interface regeneration.^70,71 Finally, advanced tissue engineering and delivery technologies, including 3D-printed bioscaffolds, long-acting microparticle release systems, and in situ cross-linked hydrogels, prolong intra-articular drug retention and modulate release kinetics, yet these approaches necessitate deeper evaluation regarding their adaptability to individual anatomical variations, the long-term biocompatibility of degradation products, and scalable manufacturing.⁷²

However, despite continuous advances in therapeutic modalities, the multi-layered barrier system arising from the inherent physiological and biomechanical architecture of the intra-articular microenvironment fundamentally limits the efficacy of these interventions.⁷³ Locally administered small molecules and biologics exhibit transient intra-articular half-lives, driven by rapid lymphatic drainage and clearance through the highly vascularized synovium.⁷⁴ In weight-bearing joints such as the knee, physiological biomechanical loading accelerates this clearance via a hydrodynamic pumping mechanism. Alterations in the non-Newtonian viscosity of synovial fluid exacerbate this therapeutic loss, while the high viscosity of healthy fluid naturally limits drug diffusion, arthritic inflammation triggers the enzymatic degradation of hyaluronic acid.^75,76 This depolymerization converts the fluid into a low-viscosity state, dismantling its physical buffering capacity and accelerating convective wash-out. Systemic administration offers little recourse, as the restrictive blood-joint barrier necessitates supra-therapeutic dosing that frequently induces systemic toxicity. Retaining a therapeutic agent within the joint space does not guarantee efficacy, given that the dense, avascular, and negatively charged extracellular matrix of articular cartilage presents significant steric and electrostatic resistance to deep chondrocyte penetration.⁷⁷ This structural barrier is compounded by a hostile inflammatory microenvironment characterized by severe hypoxia, localized acidosis, and robust reactive oxygen species generation, which rapidly denature unshielded molecules. These limitations are further modified by anatomical scale. Small extremity joints present strict volumetric constraints that trigger acute intra-articular pressure spikes upon injection, whereas the lower temperature of the first metatarsophalangeal joint accelerates monosodium urate crystallization, forming physical obstructions to drug delivery.⁷³

Consequently, overcoming these multifaceted barriers necessitates a shift from conventional unshielded monotherapies toward advanced, microenvironment-responsive delivery systems. Multifunctional nanozymes represent a pivotal innovation. By integrating multi-enzyme catalytic homeostasis restoration with targeted cargo delivery, they effectively circumvent physiological barriers to achieve sustained, disease-modifying outcomes.

Engineering Design of Nanozymes in Arthritis Therapy

Nanozymes: From Inorganic Nanoparticles to Single-Atom Catalysts

The development of nanozymes originated from the seminal discovery of intrinsic peroxidase-like activity in ferromagnetic nanoparticles.⁷⁸ These materials were later formally defined by Wei and Wang as nanomaterials that strictly adhere to Michaelis-Menten kinetics.⁷⁹ However, the clinical application of first-generation inorganic nanozymes, such as CeO₂, was often limited by catalytic heterogeneity and low atomic utilization (Figure 2a).⁸⁰ To overcome these constraints, researchers began focusing on structural diversification to enhance both biocompatibility and multifunctionality. Second-generation nanozymes employ diverse structural designs to meet the complex requirements of the articular environment.⁸¹ For instance, carbon-based nanomaterials like carbon dots utilize π-conjugated electronic systems to enable integrated photothermal theranostics (Figure 2b).⁸² Simultaneously, Metal-Organic Frameworks (MOFzymes) provide high porosity to optimize substrate diffusion within viscous synovial fluid (Figure 2c).⁵² These MOFs function as “molecular cages” that facilitate synergistic drug delivery for arthritis management. Single-Atom Nanozymes (SAzymes) represent the current peak of catalytic efficiency in this field. This superior performance arises from the dispersion of catalytic metal centers to the atomic limit, which achieves nearly 100% atom economy.⁸³ Furthermore, SAzymes are engineered with precise M-Nx coordination environments, such as Fe-N₄ centers, to mimic the structures of natural metalloenzymes (Figure 2d–f).^84–86 By replicating the geometric and electronic features of heme, these materials offer highly specific catalytic activity. Recent advancements in dual-atom engineering have further optimized the catalytic potential of these platforms. For example, Cu-Mn synergy is used to modulate the d-band center of active sites, which significantly lowers the activation energy for ROS scavenging.⁸⁷ This evolutionary trajectory reflects a fundamental paradigm shift from discovering catalytic activity to customizing it for specific needs. Recognized by IUPAC as a top emerging technology, these rationally designed atomic sites now provide a robust material foundation for precision arthritis therapy.

Figure 2 (a) Top view (left) and side view (right) of the CeO2 structural model. Atomistic-level catalytic mechanisms for the CAT-mimicking reactions of nanoceria. Adapted with permission.80 Copyright 2019, Royal Society of Chemistry (b) Synthesis of Se-CQDs with green fluorescence by the hydrothermal treatment of selenocystine. Adapted with permission.82 Copyright 2017, John Wiley and Sons (c) Typical biosafe MOFs include MIL-100(Fe)-NH2, MIL-101(Fe), ZIF-8(Zn) and UiO-66(Zr). Fe, Zr and Zn polyhedra are in Orange or red, blue, and pink, respectively. Adapted with permission.52 Copyright 2025, John Wiley and Sons (d) CoN4. Adapted with permission.84 Copyright 2018, Elsevier; (e) Structure of different SACs: FeN4.85 Adapted with permission. Copyright 2017, Wiley-VCH; (f) AuN4. Adapted with permission.86 Copyright 2019, Wiley-VCH.

Enzyme-Mimetic Catalytic Mechanisms

Nanozyme therapeutic efficacy arises from recapitulating endogenous antioxidant defenses through precise material engineering.(Figure 3).⁵ SOD-mimics utilize reversible metal redox cycles, such as Ce³⁺/Ce⁴⁺ valence switching in ceria nanoparticles, to catalyze the dismutation of superoxide anion radical (O₂^•−).⁸⁸ At the atomic scale, electronic modulation determines this efficiency. Specifically, Fe-Cu dual-atom configurations enhance activity by upshifting the d-band center, thereby optimizing O₂^•− adsorption kinetics. Consequently, these electronic adjustments lower protonation energy barriers and facilitate the efficient removal of reactive species.⁸⁹

Figure 3 Schematic representation of the main enzyme-like activities of nanozymes. Reproduced with permission.5 Copyright 2025, American Chemical Society.

SOD activity constitutes the primary antioxidant defense, yet exclusive reliance on it triggers hydrogen peroxide (H₂O₂) accumulation. Excess H₂O₂ risks conversion into cytotoxic •OH via the Fenton reaction.⁹⁰ Incorporating CAT-like activity is therefore essential for a comprehensive therapeutic strategy.⁶ Nanozymes like MnO₂ or Prussian Blue decompose H₂O₂ while evolving O₂ to alleviate synovial hypoxia. The POD-like activity exerts a synergistic effect by utilizing endogenous reducing substrates present in the microenvironment, such as glutathione (GSH), ascorbic acid, and even thiol groups of certain proteins, to catalyze the decomposition of H₂O₂ into water and oxidized substrates. This in situ reoxygenation downregulates the HIF-1α pathway and suppresses metabolic inflammation.⁹¹ Se-based GPx mimics further mitigate oxidative damage by detoxifying organic peroxides. Surface selenium centers undergo reversible redox cycling between selenol (-SeH) and selenenic acid (-SeOH). Using endogenous GSH as an electron donor, these mimics reduce toxic peroxides to benign alcohols. Consequently, this catalytic process arrests lipid peroxidation and prevents chondrocyte ferroptosis.⁹²

Advanced “cascade defense systems” address multifaceted oxidative stress through two strategic approaches. First, heterostructures or all-in-one atomic frameworks integrate multi-enzyme activities to ensure the instantaneous conversion of intermediates into H₂O and O₂. Second, metabolic cascades, such as NIR-responsive SAzymes, modulate mitochondrial respiratory chain complexes. This dual strategy scavenges existing ROS while effectively inhibiting de novo generation.⁹³

Design for Joint Environments

Engineering Strategies for Articular Nanozyme Delivery

The superior physicochemical stability of nanozymes provides the fundamental basis for their therapeutic efficacy within the intra-articular cavity. Unlike natural enzymes that are susceptible to proteolytic degradation, nanozymes maintain catalytic integrity even amidst local biochemical stressors.⁹⁴ To maximize intra‑articular retention, researchers have exploited size‑exclusion effects and bioadhesive interactions to achieve passive targeting. For instance, hydrogel encapsulation serves as a robust depot system that enables sustained release of nanozymes while concurrently imposing physical barriers against lymphatic drainage.⁹⁵ Similarly, micron‑sized aggregation or microsphere encapsulation leverages the size‑dependent clearance threshold of synovial tissue. Particles exceeding approximately 500 nm exhibit significantly prolonged retention compared to smaller counterparts, owing to reduced lymphatic uptake.⁹⁶

Beyond passive strategies, active recognition and targeting emerge when nanozyme surfaces are functionalized with ligands designed to specifically bind overexpressed receptors or characteristic components within the inflamed joint. Hyaluronic acid modification confers CD44-targeting capabilities to nanozymes, facilitating preferential accumulation in activated synovial fibroblasts and macrophages.^97,98 Folic acid functionalization exploits the elevated expression of folate receptor β (FRβ) on activated macrophages in RA and OA.^99,100 RGD peptide modifications directly target the upregulated integrin αvβ3 on angiogenic endothelium and synovial fibroblasts.¹⁰¹ Meanwhile, advances in cell membrane coating technology endow nanozymes with both active targeting capability and innate immune evasion as well as proteolytic protection. PEGylation and biomimetic coatings (eg, macrophage or platelet membranes) construct a protective barrier around the catalytic core, thereby maximizing circulation persistence and intra-articular retention.^35,102–104

The dense synovial lining and the avascular, negatively charged cartilaginous matrix present formidable biological barriers to deep nanozyme penetration. To address these challenges, researchers have explored size‑reduction strategies (eg, sub‑50 nm nanozymes) to facilitate traversal through synovial fenestrations,^105,106 while employing cationic surface modifications to enhance electrostatic binding to the negatively charged cartilage extracellular matrix.¹⁰⁷ In addition, conjugating cartilage-targeting peptides like WYRGRL to the nanozyme surface endows these therapeutics with a specific affinity for structural cartilage components.¹⁰⁸ This targeted approach enables enhanced accumulation within avascular cartilaginous zones that remain difficult to access via conventional drug delivery modalities.

Intelligent Stimulus-Responsive Design

The acidic nature of the arthritic microenvironment is characterized by synovial pH values of approximately 6.5 and intralysosomal pH below 5.2.¹⁰⁹ Utilizing this acidic gradient, pH-sensitive nanozymes can be constructed to achieve site-specific drug release and catalytic activity activation at the lesion site, enabling precise remodeling of the articular microenvironment. A representative example is the Ce‑MOF@CaCO₃ (Ce‑Ca) platform, which orchestrates a pH-responsive cascade: the CaCO₃ shell dissolves at pH 5.5, simultaneously neutralizing local acidity and releasing Ca²⁺ ions to promote subchondral bone repair; subsequently, the exposed Ce‑MOF core exerts SOD/CAT-mimetic activities, eliminates extracellular ATP to inhibit M1 macrophage pyroptosis, and generates adenosine to drive M2 repolarization.¹¹⁰ Complementing this design, the Se/LDH@PEG‑M system exploits joint acidosis to trigger degradation and release Mg²⁺, Se, and Mito-TEMPO, thereby restoring mitochondrial respiratory activity and correcting glycolytic reprogramming through GPx-mimetic catalysis.¹¹¹ Taking multi-stage response kinetics a step further, the PCM@MnO₂ system employs pH-dependent dissociation of its polydopamine (PDA) shell at pH 6.5 to enable targeted cellular binding, whereas subsequent lysosomal core degradation at pH 5.2 triggers both methotrexate burst release and MnO₂-catalyzed in situ oxygenation, collectively reversing the pro-inflammatory macrophage phenotype (Figure 4).¹⁰⁹

Figure 4 Schematic Diagram of the pH-Responsive PCM@MnO2 System. (A): Application of PCM@MnO2 NPs in RA treatment and related mechanisms. Under RA acidic conditions, PDA was degraded from PCM@MnO2 NPs to scavenge reactive oxygen species (ROS). CM@MnO2 NPs were internalized by macrophages through interaction between CS and CD44. Under intracellular conditions of low pH, CM@MnO2 NPs disintegrated to release MnO2 and MTX, which could produce O2 and inhibit inflammatory factors, respectively. PCM@MnO2 NPs effectively treated RA by improving the oxidative stress microenvironment. (B): In vitro release of MTX from PCM@MnO2 NPs at different pHs. (C): PCM@MnO2 NPs induced M1-to-M2 polarization (iNOS (yellow)↓; CD206 (red)↑).109 Copyright 2025, Springer Nature.

Beyond pH responsiveness, pathologically elevated ROS levels serve as equally sensitive switches for on-demand drug release.¹¹² The thioacetal-linked CP‑GA‑PKP nanosystem undergoes ROS-specific cleavage, shedding its polyethylene glycol (PEG) shield to expose an adhesive PDA core for enhanced intra-articular retention. Concurrently, the released gallic acid synergizes with the exposed Ce-MOF-Pt dual catalytic centers to execute SOD- and CAT-like activities, effectively scavenging superoxide radicals and hydrogen peroxide.¹¹³ In acute GA, macrophage membrane-coated HMPB‑Pt@MM nanozymes achieve homologous targeting to inflamed joints, scavenging ROS/•OH and mimicking urate oxidase to convert insoluble uric acid into allantoin, thereby eliminating crystals and alleviating hypoxia.¹¹⁴

Hypoxia represents a critical pathological hallmark of both RA and OA.¹¹⁵ Synovial hyperplasia, coupled with inflammatory cell infiltration, drives a precipitous decline in intra-articular oxygen tension (to as low as 2–4%), which in turn stabilizes HIF‑1α and upregulates VEGF, thereby promoting pannus formation and cartilage erosion.¹¹⁶ The Au@CeO₂ Nano heterojunction leverages the Localized Surface Plasmon Resonance (LSPR) effect of its gold core under NIR irradiation to generate local hyperthermia, accelerating CAT-mimetic O₂ evolution from its ceria shell and suppressing HIF‑1α/VEGF.¹¹⁷ Similarly, Macrophage microvesicle-modified amorphous MnO₂ (MMV‑MnO₂@DSP) targets deep inflammatory cartilage and synoviocytes, converting H₂O₂ to dissolved O₂ to reverse glycolytic reprogramming and modulate subchondral bone.¹⁰⁹

Beyond pH and ROS, overexpressed MMPs serve as specific enzymatic switches: TGMS-modified lipid nanomicelles enable instantaneous drug burst release exclusively during high-MMP disease flares while remaining stable during remission to prevent systemic leakage.^118,119 Consequently, Intelligent, stimuli-responsive designs further enhance the precision of nanozyme therapy, which is particularly advantageous for reducing systemic side effects and improving in vivo biosafety.

Nonetheless, current research on smart responsive nanozymes for arthritis remains constrained by significant limitations. Contemporary designs indiscriminately apply “ROS scavenging” strategy. Physiological ROS, serving as essential second messengers for intracellular signaling and redox homeostasis, cannot be exhaustively depleted without risking microenvironmental disruption. Nevertheless, systematic quantification of in vivo catalytic thresholds remains largely absent. Furthermore, the M1/M2 macrophage repolarization observed in cell cultures or rodent models may prove overly reductionist when extrapolated to the highly heterogeneous and temporally dynamic human arthritic joint. These models inadequately address the multidimensionality of the synovial immune microenvironment, the continuum of macrophage activation states, and the complex pathological feedback circuits that sustain chronic inflammation.

Applications of Nanozymes in Arthritis Therapy

Rheumatoid Arthritis (RA)

The RA microenvironment is characterized by a self-sustaining cascade of persistent inflammatory infiltration, hypoxia, and excessive reactive oxygen species (ROS) accumulation that drives bone and cartilage destruction.¹²⁰ Traditional anti-rheumatic therapies have proven effective in clinical practice, yet they rarely disrupt this vicious feedback loop. Nanozymes, with their superior stability and responsive multi-enzyme mimetic activities, enables targeted microenvironmental remodeling and precision joint theranostics. In the context of RA, they primarily serve as immunomodulators and hypoxia relievers, counteracting autoimmune-driven synovial hyperplasia and T-cell dysregulation through ROS scavenging, HIF-1α suppression, and NETs degradation. This section systematically reviews recent advances in nanozyme-mediated RA therapy across four dimensions: redox homeostasis restoration, immunomodulation, tissue repair, and multifunctional synergistic treatment (Table 1).

Table 1 Nanozyme Therapy for Rheumatoid Arthritis (RA)

Remodeling the Oxidative Microenvironment

Targeting the core pathological hallmarks of rheumatoid arthritis, the design strategy for nanozymes has evolved into a synergistic system that integrates both ROS scavenging and in situ oxygen generation. By mimicking the catalytic cascade reactions of natural antioxidant enzymes, these nanozymes achieve systematic depletion of excessive ROS, thereby effectively suppressing the cascade activation of key inflammatory signaling pathways—such as NF-κB, MAPK, NLRP3/caspase-1, cGAS-STING, and JAK/STAT—and ultimately reshaping the homeostasis of the articular immune microenvironment. Specifically, Kim et al developed MFC-MSNs utilizing manganese ferrite to decompose H₂O₂ via the Fenton reaction within H₂O₂-rich environments, generating O₂ to alleviate tissue hypoxia while incorporating ceria to scavenge hydroxyl radicals (•OH), thereby achieving synergistic ROS elimination and oxygenation (Figure 5).¹²¹ This strategy was subsequently extended to hydrogel scaffolds like MnCoO and MXene to effectively alleviate hypoxia.^125,144 These materials significantly enhance the survival and differentiation of bone marrow mesenchymal stem cells (BMSCs). Furthermore, integrating Mn₃O₄ with polydopamine (PDA) or thermosensitive liposomes enables a synergy of photothermal therapy (PTT), chemotherapy, and ROS scavenging.¹⁴³ Consequently, these multi-modal platforms provide comprehensive microenvironmental regulation.^22,145

Figure 5 (A): Therapeutic mechanisms of MFC-MSNs in RA treatment. MFC-MSNs synergistically scavenge ROS and generate O2; Promotes macrophage repolarization; Capable of loading methotrexate. (B): Synergistic ROS scavenging and O2 generation by MFC-MSNs compared with MFMSNs and C-MSNs. (i) H2O2 degradation curves in the presence of MF-MSNs, C-MSNs, and MFC-MSNs at pH 7.4 (n = 3). Estimated H2O2 degradation of MFC-MSNs was obtained by adding the degraded H2O2 concentrations of MF-MSNs and C-MSNs. (ii) O2 generation curves in 1 M H2O2 solution in the presence of NPs under physiological conditions (n = 3). (iii) SOD activity of MF-MSNs, C-MSNs, and MFC-MSNs (n = 3). (iv) Time-dependent hydroxyl radical generation of MF-MSNs, C-MSNs, and MFC-MSNs in the presence of H2O2 (n = 3). Reproduced with permission.121 Copyright 2026, ACS Nano.

Cerium-based nanozymes serve as classical antioxidants, exhibiting dual SOD- and CAT-like activities via the Ce³⁺/Ce⁴⁺ redox couple. For example, Zhou et al⁹⁸ integrated cerium oxide with ROS-responsive micelles to facilitate gated drug release and inhibit inflammatory signaling, specifically by suppressing IκB degradation and p65 nuclear translocation, thereby blocking the NF-κB pathway. To accommodate the specific intestinal environment, Wang et al¹³⁹ modulated the valence state of Au/CeOX via gold deposition to design a nanozyme with an “OXD-SOD-POD” cascade that selectively suppresses CAT activity, thereby scavenging ROS while avoiding oxygen generation to preserve anaerobic intestinal conditions.

Beyond cerium, noble metal nanozymes offer superior broad-spectrum antioxidant performance. For instance, PtTe heterostructures (HPT)⁹⁷ and CeO₂-Pt Janus nanoplatforms¹²⁹ utilize high-density Pt active sites for enhanced ROS scavenging. Furthermore, integrating multiple noble metal, such as the PtPdCo trimetallic nanozyme developed by Zhang et al, can simultaneously achieve SOD, CAT, POD, and AAO activities, thus significantly broadening the catalytic spectrum.¹⁴²

To maximize this catalytic efficiency, recent studies have transitioned toward single-atom catalysis. Incorporating atomically dispersed active sites, such as in copper single-atom-loaded graphene quantum dots or Pd single-atom-modified selenium nanomotors, significantly lowers reaction energy barriers and accelerates electron transfer.^131,133 Consequently, single-atom engineering provides a robust strategy for drastically improving nanozyme performance.

Similarly, iron-based materials like ferrihydrite nanoparticles have been optimized for targeted ROS conversion.¹⁰⁶ While traditional iron nanozymes rely on basic nanocatalytic mechanisms, recent advancements focus on elevating biosafety alongside efficiency. By mimicking natural protein folding, Yang et al designed a biomimetic peptide single-chain artificial enzyme. Ultimately, this structural innovation achieves high SOD/POD-like activity while maintaining extremely low iron loading (<5%).¹⁴⁰

Remodeling the Immune Microenvironment

Restoring synovial immune homeostasis, primarily by repolarizing macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, is a central therapeutic objective in RA management. Nanozymes facilitate this phenotypic reprogramming through ROS scavenging, metabolic modulation, and synergistic pharmacological interactions. By mitigating oxidative stress and hypoxia, nanozymes effectively inhibit pro-inflammatory signaling pathways—including NF-κB, MAPK, and JAK-STAT—thereby fostering M2 polarization.^{103,121,126,127,142}

To advance this immune reprogramming, researchers have developed multifunctional nanoplatforms that target both innate and adaptive immunity. For example, the ceria-mesenchymal stem cell nanovesicle hybrid system (Ce-MSCNVs) engineered by Koo et al promoted M2 polarization and induced regulatory T cell (Treg) differentiation to restore immune equilibrium.¹²⁸ Similarly, ROS-responsive micelles developed by Zhou et al⁹⁸ synergistically suppressed TLR4 signaling by co-delivering rhein and cerium ions, which concurrently inhibited p65 phosphorylation and IκBα degradation to block NF-κB activation, downregulate IL-1β and TNF-α transcription, and subsequently suppress JAK2/STAT1 phosphorylation. To ensure long-term efficacy, Zhang et al¹⁴² incorporated chloroquine into their system to inhibit ferroptosis in M2 macrophages during transition, effectively preserving the stability of the anti-inflammatory phenotype.

Beyond phenotypic modulation, directly scavenging or sequestering pathogenic factors within the microenvironment serves as a crucial complementary strategy. For instance, Jin et al¹³⁴ designed a biomimetic nanogel integrating ceria nanozymes with DNase I to simultaneously scavenge ROS and degrade Neutrophil Extracellular Traps (NETs). Moreover, macrophage membrane-coated nanoparticles have proven highly effective as broad-spectrum “decoys” to neutralize pro-inflammatory cytokines and mediators.^103,104 To further guide these interventions, Niu et al¹³⁷ developed electrochemical sensors for the high-sensitivity detection of autoantibodies (eg, Anti-MCV), enabling crucial early-stage therapeutic timing. Ultimately, coupling early immune detection with targeted environmental neutralization comprehensively arrests the inflammatory cascade.

Tissue Repair and Regeneration

To address the irreversible osteochondral destruction in RA, nanozyme applications have expanded into regenerative tissue engineering. Functionalized hydrogel scaffolds, for example, are now engineered to recapitulate specific articular anatomies. Hu et al developed a LiMn₂O₄ nanozyme-loaded bilayer hydrogel that biomimetically simulates the cartilage and subchondral layers, thereby promoting the synergistic regeneration of both tissues.¹⁴⁶ Integrating functional mitochondria with Prussian blue nanozymes within a DNA hydrogel facilitates efficient tissue repair by restoring cellular energy metabolism.¹³⁸ Furthermore, a copper single-atom nanozyme hydrogel combines anti-inflammatory effects with a specialized lubricating network. This design effectively mitigates friction-induced mechanical damage and ensures robust long-term adhesion (Figure 6).¹³³

Figure 6 (A) Synthesis of DAGQD@Cu SAN and DAGQD@Cu@KGN SAN. (B) Synthesis of DAGQD@Cu@KGN-SO3−/DA-HA hydrogel. (C) DAGQD@Cu@KGN-SO3−/DA-HA hydrogel for RA therapy. (I) Hydrogel self-cures in situ within the joint cavity; (II, III) DAGQD@Cu@KGN-SO3−/DA-HA hydrogel displays lubrication and adhesion properties; (IV) Regulation of inflammatory microenvironment facilitated by SAN with remarkable ROS-scavenging capabilities; (V) KGN released from the hydrogel promotes the recruitment of BMSCs and induces their differentiation into chondrocytes, facilitating the repair of cartilage damaged by RA. Reproduced with permission.133 Copyright 2025, Springer Nature.

Parallel to hydrogel development, advances in implant surface engineering and cell-based therapies have further enhanced osteochondral regeneration. For instance, applying a MnFe₂O₄ coating to titanium substrates successfully induces immunomodulatory osseointegration.¹³⁰ This process is driven by the reprogramming of macrophage mitochondrial metabolism from glycolysis to oxidative phosphorylation. Additionally, augmenting mesenchymal stem cells (MSCs) with nanozymes provides crucial antioxidant protection.¹²⁴ This intracellular modification enhances MSC survival, fosters M2 polarization, and accelerates subsequent cartilage repair. Beyond localized joint interventions, current research also explores systemic modulation via the “microbiota-gut-joint axis.” Adopting this macroscopic perspective, researchers have developed orally administered, valence-tunable Au/CeO₂ nanozymes.¹³⁹ These unique agents scavenge intestinal ROS while actively suppressing oxygen generation to preserve strict anaerobic homeostasis. By subsequently modulating short-chain fatty acid metabolism, this mechanism achieves remote, systemic therapeutic efficacy against RA.

Multi-Functional Platform

Nanozymes are increasingly serving as pivotal hubs for integrating physical modalities, pharmacotherapy, and diagnostic imaging. In physical field-assisted therapies, for example, coupling PTT with nanozymes effectively mitigates heat-induced oxidative stress. Materials such as Pt-Te, Pd, carbon-based nanostructures, and Mn₃O₄ leverage their photothermal conversion capabilities to generate localized hyperthermia under near-infrared (NIR) irradiation. This process thermally ablates inflammatory macrophages while synergistically accelerating enzymatic ROS scavenging.^{22,97,103,143} Similarly, combining sonodynamic therapy (SDT) with sonosensitizer-conjugated rhodium nanozymes couples ultrasound-triggered ROS generation with self-oxygenation, utilizing human serum albumin for active targeting.¹²² Therefore, integrating external physical stimuli with intrinsic nanozyme catalysis achieves mutually reinforcing therapeutic outcomes.

To complement these physical therapies, nanozymes also facilitate the seamless convergence of chemotherapy and catalytic therapy. This versatility is largely due to their intrinsic porous or hollow architectures, which render them superior drug delivery vehicles. Therapeutic agents, such as methotrexate,^22,121,143 dexamethasone,¹²⁷ rapamycin¹³⁶ and iguratimod,^103,141 are frequently encapsulated and released via engineered pH- or ROS-responsive mechanisms. Beyond traditional small molecules, these carriers also enable combined gene-chemotherapy; for instance, complexing HIF-1α siRNA with calcium phosphate transcriptionally blocks hypoxia signaling.¹²³ Nanozymes provide highly adaptable platforms for precise, stimulus-triggered multimodal treatments.

Beyond therapeutic delivery, integrating diagnostic and imaging capabilities enables the real-time monitoring of treatment efficacy. Theranostic nanozyme platforms routinely incorporate advanced techniques such as NIR-II fluorescence,¹²⁹ magnetic resonance imaging (MRI),¹⁰⁵ and photoacoustic imaging.¹²¹ Moreover, nanozyme-based sensors allow for the ultrasensitive detection of RA biomarkers like anti-MCV¹³⁷ and therapeutics such as D-penicillamine¹³² aiding in both early diagnosis and therapeutic monitoring.

Osteoarthritis (OA)

The pathophysiology of OA is multifaceted. It is characterized by an intricate interplay of oxidative stress, chronic inflammation, chondrocyte metabolic dysregulation, and ECM degradation. While natural antioxidant enzymes (eg, SOD, CAT) offer theoretical regulatory potential, their clinical utility is frequently compromised by inherent instability within the harsh pathological microenvironment. Conversely, nanozymes possess stability and tunable multi-enzyme mimetic capabilities, encompassing SOD-, CAT-, and GPx-like activities. For OA, these properties frame nanozymes as chondroprotective agents that focus on mitochondrial quality control, Nrf2 activation, and cartilage matrix preservation to counteract the degenerative and senescence-associated pathology. Therefore, nanozymes have transcended the role of passive ROS. They have evolved into active disease-modifying agents capable of precisely remodeling organelle function and the immune microenvironment (Table 2).

Table 2 Nanozyme Therapy for Osteoarthritis (OA)

Redox Homeostasis Remodeling

Excessive ROS accumulation drives chondrocyte senescence, apoptosis, and ECM degradation in OA. Consequently, engineering nanozymes that mimic natural antioxidants constitutes a primary therapeutic strategy. Metal oxide nanozymes, such as Mn₃O₄, exhibit robust, broad-spectrum catalytic properties, specifically dual SOD- and CAT-like activities, that significantly attenuate intracellular ROS. Thus, these metal-based systems effectively preserve cartilage integrity.^152,156,172 To mitigate the inherent cytotoxicity of bare metal oxides, surface coatings have been employed to minimize cytotoxicity while retaining high catalytic efficiency, such as PDA coating on Cr2O3 and Mn₃O₄.^171,172 Structural design serves as a crucial strategy to further amplify the catalytic efficiency of nanozymes. Defect-rich hollow RuO₂ nanospheres (d-RuO₂) leverage their amorphous and hollow architecture to maximize active site exposure, surpassing crystalline equivalents.¹⁷⁴ Beyond macroscopic architectures, engineering at the atomic level provides additional enhancements. Specifically, synergistic dual-atom Fe-Fe sites directly amplify ROS clearance capacity (Figure 7).¹⁷⁹ Similarly, cobalt single-atom-doped platinum nanozymes (Pt/Co-SA-NSG) exhibit augmented SOD/CAT-mimetic activities.¹⁵⁴

Figure 7 (A): Schematic synthesis and mechanism illustration of Fe2-NCs, which perform as SOD, CAT, and GSH-Px to sequentially scavenge ROS and GSH for mitigating OA. (B): Bioinspired catalytic defense mechanism: Nanozyme-mediated sequential ROS scavenging mimicking SOD, CAT, OXD, and GPx enzymatic cascades. Reproduced with permission.179 Copyright 2025, Wiley-VCH GmbH.

Due to their structural tunability, metal-organic frameworks (MOFs) have emerged as prominent scaffolds for antioxidant nanozymes. Copper-based MOFs, for example, have been engineered as safe nanozymes offering comprehensive antioxidant protection (SOD/CAT/•OH scavenging) devoid of pro-oxidant side effects.¹⁶⁵ Prussian blue (PB) analogues constitute another major class, with both ultrasmall (3.5 nm) PB nanozymes¹⁶¹ and hollow manganese-PB variants¹⁴⁹ exhibiting exceptional ROS scavenging and hypoxia-mitigating capabilities. Furthermore, integrating PB into self-hydrogen-releasing platforms achieves synergistic oxidative stress alleviation via concurrent H2 therapy and enzymatic catalysis.¹⁷⁶ To further enhance biocompatibility and targeting specificity, diverse surface modification strategies have been adopted. For instance, lubricin-inspired PAF nanozymes (PAMPS-grafted amino-fullerene)¹⁵⁸ and Pluronic F127-coated Prussian blue¹⁵⁰ have successfully improved material stability and cellular uptake. Moreover, stimuli-responsive systems have also been developed, such as a ceria-based “mitochondria inspector” that enables the on-demand, ROS-triggered release of SOD/CAT-mimetic CeNPs for precise oxidative stress intervention.¹⁶⁷

Immune Microenvironment Remodeling

OA is increasingly recognized not merely as a degenerative wear disorder but as a complex inflammatory pathology. Within this context, nanozymes remodel the joint immune microenvironment primarily by directing macrophage polarization, shifting the phenotype from pro-inflammatory M1 to anti-inflammatory M2 states. Extensive evidence corroborates that nanozymes modulate this plasticity via ROS scavenging, which subsequently suppresses key inflammatory cascades including NF-κB, MAPK, and JNK. For example, ultrasmall Prussian blue nanozymes,¹⁶¹ hollow Prussian blue analogs,¹⁴⁹ and PdZn/CoSA-NC nanozymes¹⁶⁴ effectively induce this transition, decreasing pro-inflammatory markers (eg, iNOS, TNF-α) while elevating anti-inflammatory mediators (eg, Arg-1, IL-10). Mechanistically, PdZn/CoSA-NC nanozymes also inhibit M1 activation through purine metabolism modulation.¹⁶⁴

Integrating nanozymes with bioactive molecules establishes a dual-action paradigm that couples antioxidative capacity with targeted immunomodulation. For instance, CeO₂ nanozyme-mediated self-assembly of rhein hydrogels synergistically suppresses the IL-6/JAK2/STAT1 axis.¹⁷⁰ Similarly, Xu et al¹⁷⁷ developed a Zinc–Loureirin B (Zn-LB) coordination nanozyme enhanced both drug bioavailability and immunomodulatory efficacy. Additionally, Yang et al¹⁷⁸ engineered a biomimetic nanoplatform incorporating anti-inflammatory peptide (KAFAK) and macrophage-synoviocyte hybrid membrane coating, achieving dual-targeted therapy against synovitis and cartilage degradation.

At the molecular level, rationally designed nanozymes exert anti-inflammatory efficacy by intercepting specific signaling cascades. Key examples include the targeted blockade of JNK phosphorylation and NF-κB signaling,¹⁵⁰ alongside the dual inhibition of the ROS-NF-κB and MAPK pathways.¹⁵⁷ Additionally, hollow Prussian blue nanozymes mitigate inflammation and apoptosis via Rac1/NF-κB axis suppression.¹⁴⁷ Ultimately, these precise molecular interventions profoundly ameliorate the osteoarthritic inflammatory microenvironment.

From Mitochondrial Repair to Tissue Repair

Recent advances in OA pathophysiology highlight subcellular targeting as the next frontier in nanozyme therapeutics. Because mitochondrial dysfunction initiates chondrocyte senescence and apoptosis, conjugating targeting moieties, such as triphenylphosphine (TPP), enables precise organelle localization. For example, Mn₃O₄/UIO-TPP nanozymes effectively scavenge mitochondrial ROS. This targeted intervention restores membrane potential and preserves mitochondrial DNA (mtDNA) integrity.¹⁵⁶ Intervening in pathological mitochondrial cascades represents a vital homeostatic strategy. To combat respiratory chain impairment, the HTM-N@Gel NAD+/O₂ co-delivery system restores mitochondrial bioenergetics by synchronously replenishing electron donors and acceptors (Figure 8).¹⁷⁵ Furthermore, active intervention in pathological mitochondrial pathways represents an emerging trend. Notably, the “Mitocelle” Prussian blue nanozyme developed by Lim et al¹⁷³ mitigates ROS generation at its source by competitively inhibiting the NOX4-p22phox interaction.

Figure 8 Design of the cartilage-mitochondria cascade-targeting composite hydrogel and its therapeutic mechanism for OA. (a) Synthesis of mitochondrialtargeting functionalized MnO2-based nanozymes. (b) Fabrication of cartilage-targeting interpenetrating network hydrogel microcarriers. (c) Minimally invasive intra-articular injection of the composite hydrogel, where the positively charged hydrogel surface facilitates cartilage adhesion, followed by the in situ release of mitochondrial-targeting functionalized MnO2-based nanozymes. This process mitigates oxidative stress-induced chondrocyte senescence, thereby inhibiting OA progression. Reproduced with permission.175 Copyright 2025, Elsevier.

The elimination of dysfunctional mitochondria via mitophagy is critical for maintaining chondrocyte homeostasis. Microsphere system assembling ceria nanozymes with metformin has been shown to activate autophagy for this purpose.¹⁶⁷ Similarly, NIR-triggered MOF nanozymes¹⁵³ and hydrogen-releasing nanozymes¹⁷⁶ have demonstrated efficacy in preserving mitochondrial function, promoting mitophagy, and retarding chondrocyte senescence. Beyond senescence mitigation, nanozymes are employed to inhibit other cell death modalities. For example, a platinum nanozyme-loaded silk fibroin/oxidized pullulan hydrogel (Pt@SF/oxPL) effectively suppressed chondrocyte ferroptosis by scavenging ROS and lipid peroxides.¹⁵⁹ Additionally, a biomimetic membrane-camouflaged nanozyme (CM@HPBPT) was found to attenuate inflammation-induced chondrocyte injury by intercepting the cGAS-STING pathway mediated by cytosolic mtDNA leakage.¹⁶⁸

Multifunctional Synergistic Therapy

To overcome the intrinsic limitations of monotherapies, researchers have developed synergistic platforms integrating nanozymes with modalities like PTT, gene interference, and drug delivery, which markedly amplifies targeted therapeutic outcomes. NIR-responsive nanozymes facilitate the synergistic coupling of PTT with enzymatic catalysis. For instance, a NIR-triggered, tea polyphenol (TP)- modified metal-organic framework (TP-Au@PCN) facilitates concurrent photocatalytic ROS scavenging and photothermally controlled drug release.¹⁵³ Similarly, Pt/Co single-atom nanozymes exhibit augmented enzymatic activity and photothermal conversion under NIR-II irradiation.¹⁵⁴ Additionally, zwitterionic nanozymes mimicking both antioxidant enzymes and hyaluronan synthase (HAS) utilize mild photothermal stimulation to upregulate heat shock protein 70 (HSP70), thereby fostering cartilage regeneration.¹⁵⁵

Nanozymes frequently function as versatile vehicles for therapeutic cargo. Combining MOF-encapsulated iridium oxide (IrO₂) nanozymes with antisense oligonucleotides (ASO) enables simultaneous ROS scavenging and miR-181a silencing to actively modulate chondrocyte metabolism.¹⁶³ Parallelly, Kartogenin-loaded nanozymes utilize precise pH-responsive release kinetics to drive the chondrogenic differentiation of mesenchymal stem cells.¹⁶⁰ Moreover, hydrogel systems incorporating platelet-rich plasma (PRP) leverage the synergy between PRP-derived growth factors and the antioxidative capacity of selenium nanozymes to achieve comprehensive “inside-out” and “outside-in” tissue repair.^70,148,169

Achieving prolonged intra-articular retention and on-demand drug release necessitates the development of intelligent hydrogel matrices. These materials are characterized by injectability, self-healing properties, and environmental responsiveness such as pH, ROS, or temperature. Prominent examples include Schiff base-crosslinked hyaluronic acid hydrogels,^162,166 silk fibroin/oxidized pullulan scaffolds,¹⁵⁹ and mitochondria-targeting NAD+/O₂ co-delivery interpenetrating networks.¹⁷⁵ Furthermore, pH- and ROS-responsive hydrogels developed by Zhou et al¹⁴⁸ and Wang et al¹⁶² respectively, have demonstrated significantly enhanced therapeutic efficacy and sustained retention.

In summary, nanozymes significantly ameliorate OA pathology through multifaceted mechanisms, encompassing ROS scavenging, immune polarization modulation, inflammatory pathway suppression, and the promotion of cartilage matrix synthesis. Preclinical studies consistently evidence improvements in histology, cytokine profiles, and locomotor function, alongside favorable biocompatibility and safety profiles. Looking forward, the integration of organ-on-a-chip models with rigorous clinical translational research positions nanozymes as a promising avenue for developing DMOADs.

Gouty Arthritis (GA)

GA pathogenesis fundamentally originates from MSU crystal deposition and the consequent sterile inflammation. While biological urate oxidase exhibits potent uricolytic activity, its clinical translation is significantly impeded by intrinsic immunogenicity and the oxidative injury provoked by its catalytic byproduct, hydrogen peroxide (H₂O₂).⁵ The advent of nanozymes represents a paradigm shift addressing these challenges. For GA, nanozymes are positioned as rapid ROS scavengers and purine metabolic regulators, with particular emphasis on NLRP3 inflammasome inhibition and uric acid metabolism modulation to terminate the MSU crystal-triggered acute inflammatory burst. Current design philosophies have transcended simple mono-enzyme mimicry, evolving into intelligent theranostic systems that orchestrate “self-cascading” catalysis, atomic-level active site engineering, and immune microenvironment reprogramming (Table 3).

Table 3 Nanozyme Therapy for Gouty Arthritis(GA)

Re-Establishing Redox Homeostasis

To circumvent the “ROS dilemma”, in which natural uricase generates hydrogen peroxide (H₂O₂) and thereby exacerbating inflammation, researchers have increasingly focused on designing bi- or multi-functional nanozymes. These integrated platforms possess intrinsic urate oxidase (UOX) alongside CAT/SOD activities, enabling simultaneous uric acid clearance and ROS elimination. For example, optimizing a Pt/CeO₂ nanozyme at a 1:5 molar ratio utilizes Pt for UOX mimicry while leveraging CeO₂ oxygen vacancies for potent CAT activity. Consequently, this synergistic design achieves the instantaneous scavenging of degradation-induced H₂O₂.¹⁸¹

Furthermore, catalytic efficiency can be amplified through precise nanostructural and morphological engineering. Xi et al synthesized ultrathin PdPt3 and PdIr3 cubic hollow nanocages (HNCs). This distinct topology maximizes active site exposure and optimizes electronic structures via alloying, thereby driving an efficient ROS scavenging cycle (Figure 9).¹⁸⁸ Additionally, Ye et al elucidated the size-dependence of catalytic activity, identifying that 46 nm two-dimensional Pd@Ir nanosheets exhibit the lowest activation energy for uric acid degradation (35.9 kJ/mol). Crucially, these nanosheets facilitate O₂ regeneration via a self-cascading reaction mechanism, effectively mitigating the hypoxic microenvironment.¹⁹⁰

Figure 9 TEM images of (A) core/shell Pd/Pt, (B) core/shell Pd/Ir nanocubes, and (C) PdPt3 and (D) PdIr3 HNCs. HR-TEM images of (E) Pd/Pt, (F) Pd/Ir nanocubes, and (G) PdPt3 and (H) PdIr3 HNCs. EDS-elemental mappings of (I) Pd/Pt, (J) Pd/Ir nanocubes, and (K) PdPt3 and (L) PdIr3 HNCs. EDS-line scans of (M) Pd/Pt, (N) Pd/Ir nanocubes, and (O) PdPt3 and (P) PdIr3 HNCs. Reproduced with permission.188 Copyright 2024, American Chemical Society.

Dissolution of Monosodium Urate Crystals

Beyond systemic uric acid clearance, directly modulating MSU crystal nucleation serves as a pivotal objective in comprehensive gout management. To this end, Liu et al constructed a biomimetic architecture mirroring natural enzyme pockets.¹⁸³ By utilizing arginine-rich peptides (protamine) to direct the growth of rhodium nanoclusters (RhNCs) on reduced graphene oxide (rGO) surfaces. This design endowed the material with exceptional substrate affinity (Km approaching that of natural enzymes) and robust physiological stability, effectively prolonging the induction period for urate crystallization. Earlier investigations by the same group corroborated that arginine peptide-guided Pt nanoclusters (ARP-PtNC) mimic the multi-enzyme cascade functions of peroxisomes, thereby suppressing the formation of needle-like crystals.^183,184

Advancing to atomic precision, the direct dissolution of mature crystals constitutes a distinct and highly effective physicochemical intervention. Lin et al developed a Mn-N-C single-atom nanozyme (P–Mn–N–C) by precisely modulating the Mn⁴⁺/Mn²⁺ redox equilibrium and the nitrogen coordination sphere.¹⁸² This nanomaterial not only exhibits triple enzyme-mimetic activity but also directly adsorbs and erode pre-existing MSU crystals via surface charge interactions. Ultimately, this atomic-level engineering provides a robust therapeutic alternative that fundamentally diverges from conventional pharmacological treatments.

Biomimetic Targeting and Immune Microenvironment Remodeling

As insights into gouty arthritis (GA) pathogenesis deepen, therapeutic paradigms have transitioned from isolated metabolic regulation to holistic immune microenvironment remodeling. To achieve precise lesion targeting while evading immune clearance, biomimetic cell membrane camouflage technologies have been widely adopted.¹⁹² By employing a Trojan horse” strategy, macrophage or erythrocyte membranes endows nanozymes with prolonged circulation half-lives and intrinsic inflammatory tropism. Specifically, macrophage membrane-cloaked Prussian blue/platinum nanozymes (HMPB-Pt@MM) exploit surface receptors (eg, LFA-1) to selectively accumulate inflamed sites.¹¹⁴ This system suppresses gout recurrence by concurrently metabolizing uric acid and driving M1-to-M2 macrophage repolarization.

To further elevate functional integration, Chen¹⁹¹ and Xu¹⁸⁹ developed sophisticated fusion membrane systems such as erythrocyte-macrophage hybrid membranes. These intelligent platforms not only serve as vehicles for uricase and anti-inflammatory agents (eg, methotrexate, resveratrol) but also integrate photothermal agents (SPIONs) or photothermal nanozymes. The resulting synergistic interplay between thermal effects and pharmacotherapy blocks the NF-κB pathway, potently inducing the M1-to-M2 transition. At the molecular level, folate-modified liposomes (FALNZs) selectively target folate receptor β-overexpressing M1 macrophages to arrest inflammatory cascades via intracellular ROS clearance.¹⁸⁵ Parallelly, biomimetic nanoparticles (BIM NPs) utilizing a MnO₂ shell scavenge ROS while releasing indomethacin.¹⁸⁶ These dual-action mechanisms comprehensively resolve inflammation by preventing neutrophil infiltration and promoting reverse migration.

The application of nanozymes in GA therapy is currently transcending traditional formulation limits, extending into implantable biomedical devices. Researchers have integrated Pt-CeO₂ nanozymes into 3D-printed meniscus scaffolds featuring gradient porosity.¹⁸⁷ This biomimetic device provides mechanical support while adaptively regulating catalytic activity in response to local uric acid levels. This innovation marks a critical paradigm shift, transitioning nanozyme therapeutics from acute pharmacological interventions to structure-function integrated tissue engineering for chronic disease management.

Challenges and Future Research

In light of the substantial evidence presented above, it is clear that researchers have accomplished a series of landmark advances in both the design and mechanistic elucidation of nanozymes, substantiating the clinical translational potential of inorganic nanozymes. Across the distinct pathological landscapes of RA, OA, and GA, recent therapeutic breakthroughs share a common paradigm encompassing multi-enzyme cascade catalysis, microenvironmental reprogramming, and hybrid biomaterial integration (Supplementary Table 1).¹⁹³ These platforms are engineered with multi-mimetic activities, specifically emulating superoxide SOD, CAT, and urate oxidase, to enable sequential reactive oxygen species (ROS) scavenging and crystal dissolution while suppressing pro-oxidant Fenton side reactions.^194,195 This catalytic relay modulates local immunometabolism, shifts the polarization of M1 macrophages and activated neutrophils toward anti-inflammatory M2 phenotypes, and subsequently dampens the inflammatory cascade.⁹⁸ To navigate the physical constraints of dense cartilage extracellular matrices and rapid synovial lymphatic clearance, these inorganic nanocatalysts are incorporated into responsive delivery vectors, such as membrane-camouflaged biomimetic vesicles, ROS-responsive polymeric micelles, and injectable hydrogel scaffolds.^88,114,161 This integration extends intra-articular retention and facilitates chondrocyte targeting, combining localized nanocatalysis with controlled drug release and osteochondral tissue regeneration.¹⁹⁶

However, translating these laboratory successes into clinical realities is hampered by a dynamic physiological reality: the joint cavity acts as an active biological barrier that counteracts external therapeutic interventions through interconnected oxidative, immune, and proliferative signals. While the inherent multi-enzyme mimetic activity of nanozymes provides a clear biochemical advantage over single-target agents, their systemic or intra-articular deployment raises pressing questions regarding structural integrity, biocompatibility, target specificity, and batch-to-batch consistency. A closer examination of these issues suggests that the current enthusiasm for nanozyme therapy may need to be tempered by a more rigorous assessment of what can realistically be achieved. Consequently, in the following discussion, we shift focus from what has been accomplished to what remains unresolved, offering a critical perspective on the barriers that lie ahead.

Long-Term Biosafety

Biosafety remains the principal impediment to the clinical translation of nanozymes.¹⁹⁷ Unlike conventional small-molecule therapeutics, these platforms frequently incorporate transition metals such as Mn, Pt, Ce, Au, and Pd. Despite this, their long-term in vivo metabolic trajectories and immune interactions remain incompletely elucidated. Surface engineering, specifically PEGylation and biomimetic cell membrane camouflaging, effectively attenuates acute immunogenicity. However, these modifications do not resolve fundamental clearance issues. Evidence indicates that certain metal-based nanozymes (eg, ceria, Prussian blue analogs) may sequester in the liver, spleen, or kidneys for extended periods.^{35,98,105,121,128,151} Compounding this issue, current literature predominantly relies on short-term rodent efficacy models spanning merely 2 to 8 weeks.^{35,122,129,134,163,166,173,180} This distinct lack of comprehensive toxicological profiling obscures our understanding of chronic metal burdens. Specifically, it is entirely unknown whether this prolonged retention precipitates organ fibrosis, chronic inflammation, or secondary oxidative injury via Fenton-mediated hydroxyl radical generation.

Beyond systemic risks, localized nanoparticle aggregation within the articular space can paradoxically exacerbate joint pathology. Large aggregates frequently trigger “frustrated phagocytosis,” a process where synovial macrophages fail to internalize the material and consequently release pro-inflammatory cytokines. This specific mechanism closely mimics the pathogenicity of monosodium urate crystals in gout.⁵ Consequently, the development of biodegradable or ultrasmall, renally clearable nanozymes, coupled with the establishment of a rigorous, full-lifecycle safety evaluation framework, encompassing reproductive and genotoxicity, is a prerequisite for clinical translation.

Catalytic and Delivery Challenges in Joint Nanozyme Therapy

Considerable efforts have been made to address nanozyme catalytic instability in the articular microenvironment, including surface engineering to enhance delivery and stimulus-responsive systems tailored to arthritic pathophysiological cues. Despite these advances, critical deficiencies remain. The formation of a protein corona upon synovial fluid exposure physically occludes active sites and compromises catalytic efficiency, while PEGylation and membrane-camouflaging strategies—though partially effective—often introduce new complexities such as reduced activity or accelerated clearance.¹⁹⁸ Furthermore, the intrinsic pH-dependence of most nanozymes creates a fundamental disconnect: optimal activity frequently occurs in acidic lysosomal compartments (pH 4.0–5.5),¹⁹⁹ yet therapeutic efficacy in OA or RA requires sustained SOD/CAT-mimetic function within the weakly acidic inflammatory milieu (pH 6.5–6.8).^147,159 Compounding these catalytic challenges, intra-articular delivery confronts the paradox of prolonged retention versus deep cartilage penetration. The dense synovial lymphatic network clears free nanoparticles within hours,²⁰⁰ while bulky hydrogel depots, though improving retention, fail to traverse the negatively charged cartilage ECM, restricting nanozymes to superficial surfaces and limiting efficacy against deep zone degeneration.^{125,133,134,138,144,146,148,159,168,169,201–203} Although ultrasmall particles or charge-reversal mechanisms enhance ECM permeability, they simultaneously sacrifice retention time.²⁰⁴ Overcoming these barriers requires three concurrent efforts: (1) the engineering of pH-insensitive broad-spectrum nanozymes through multi-metal alloying, heterojunction construction, or defect engineering; (2) the establishment of physiologically relevant activity detection systems that replicate the protein-rich and shear-stress conditions of synovial fluid; and (3) the development of multi-stage delivery systems, such as exosome-based carriers or MMP-responsive particles, that reconcile sustained retention with deep tissue penetration.

Clinical Translation and Production Standardization

Translating nanozyme synthesis from the bench to industrial scales introduces formidable Chemistry, Manufacturing, and Controls (CMC) challenges. Unlike well-defined small molecules or biologics, nanozyme catalytic efficacy depends intrinsically on complex physicochemical properties. These structural determinants encompass crystal lattice integrity, surface defect density, coordination environments, and particle size distribution. During scale-up, even minor deviations in macro-reaction parameters (eg, temperature, agitation rate) can induce profound batch-to-batch variations in catalytic performance.²⁰⁵ Establishing reproducible, industrial-grade synthetic methodologies is therefore a fundamental prerequisite for guaranteeing therapeutic consistency. Parallel to manufacturing hurdles, a profound standardization and regulatory gap impede clinical progress. The field currently lacks a unified metric or standardized unit for defining nanozymatic activity. Disparate substrates and assay conditions across laboratories confound cross-study comparability and preclude the development of precise clinical dosing regimens. Moreover, existing regulatory frameworks provide no specific guidelines for inorganic, enzyme-mimetic nanomaterials. Defining their regulatory classification demands urgent consensus between regulatory agencies and researchers, whether as drugs, medical devices, or combination products. To successfully cross the threshold into clinical trials, implementing standardized activity assays and rigorous quality control protocols remains strictly imperative.

Future Research Directions

To overcome the translational barriers outlined above, future arthritis-targeted nanozyme research must strategically advance along several interconnected frontiers. First, the vast material parameter space makes traditional trial-and-error development inefficient. Artificial intelligence, particularly machine learning trained on catalytic databases, can establish quantitative structure-activity relationships that link material properties to target enzyme-like activities, enabling rapid and cost-effective predictions of catalytic performance prior to experimental synthesis. Combining density functional theory calculations with machine learning algorithms further enables the prediction of intermediate adsorption energies on various metal oxide surfaces, offering mechanistic insights into catalytic selectivity and turnover rates.

Second, SAzymes, featuring isolated metal atoms atomically dispersed on solid supports, represent a paradigm shift toward precision catalysis, offering maximized atomic utilization and well-defined M-Nx coordination structures that facilitate precise activity regulation. Emerging evidence indicates that tuning the coordination geometry of M-Nx sites can differentially regulate catalytic selectivity, which provides the advantage of mild and controllable ROS regulation, while their atomically dispersed nature concurrently facilitates renal clearance.⁸⁹

Third, the complex, multifactorial pathology of arthritis necessitates multi-enzyme mimetic nanozymes that integrate two or more catalytic activities (eg, SOD + CAT, SOD + GPx, POD + UOD, or the complete quartet) within a single nanoplatform. Core-shell architectures and MOF-based frameworks enable spatial organization of sequential catalysis. Biomimetic camouflage represents another critical developmental direction. By integrating diverse cell membrane coatings, researchers can exploit endogenous receptor-ligand interactions to precisely target the inflamed synovium while concurrently optimizing biocompatibility. Furthermore, the therapeutic paradigm must evolve from isolated antioxidative interventions toward holistic microenvironmental reprogramming by integrating ROS scavenging with targeted delivery of pharmacological or genetic payloads to suppress core inflammatory cascades, notably NF-κB, NLRP3, and JAK-STAT.

Fourth, the heterogeneity of arthritis calls for personalized strategies stratified by synovial fluid cytokine profiles, autoantibody status, and ROS composition. Finally, clinical translation demands a clear roadmap addressing GMP-compliant manufacturing processes, regulatory classification, and the establishment of appropriate clinical trial endpoints. Addressing these unresolved issues will chart the course for future therapeutic applications.

Conclusion

While conventional pharmacotherapies offer rapid symptomatic relief, their capacity to reverse the self-sustaining inflammatory and oxidative microenvironments within arthritic joints remains inherently limited by poor local bioavailability and multifactorial pathogenesis. Nanozymes have demonstrated substantial preclinical efficacy in modulating this pathological niche, driven by their intrinsic enzyme-mimicking activities and programmable physicochemical properties. Their robust capacity to scavenge excessive reactive oxygen and nitrogen species while concurrently remodeling local immunometabolic profiles mechanistically distinguishes them from conventional single-target interventions. Despite these promising preclinical outcomes, current evidence predominantly derives from acute or early-stage animal models that fail to accurately replicate the chronic, multifactorial nature of human arthritis. The long-term intra-articular fate of inorganic nanozymes, encompassing degradation kinetics, metabolic clearance pathways, and potential off-target accumulation, remains inadequately elucidated. Intra-articular injection currently represents the most feasible near-term clinical route, yet issues of joint retention and immunological tolerance to repeated administrations must be addressed. Advancing this field requires focused attention on three critical research priorities. Systematic and prolonged biosafety evaluations in clinically relevant animal models, particularly utilizing immunocompetent, aged, or comorbid subjects, must precede any clinical translation. Mechanistic investigation of synovial clearance and cartilage penetration. And developing active targeting strategies is critical for establishing sufficient therapeutic concentrations within the avascular zones of articular cartilage. Nanozymes offer a conceptually distinct and mechanistically feasible complement to existing arthritis therapeutics, exhibiting the potential to address unmet needs. Realizing this theoretical potential demands rigorous validation through comprehensive in vivo profiling and meticulously designed translational studies. The ultimate clinical realization of nanozyme strategies hinges not merely on their catalytic efficacy, but fundamentally on their safety, biocompatibility, and deliverability—the primary foci of ongoing and future research endeavors.