Nanotherapeutic Strategies for Osteoarthritis: Targeting Aging, Metabolism and Inflammation

Introduction

Osteoarthritis (OA) is the most common type of arthritis and a major contributor to joint pain and disability, impacting over 7% of people worldwide (528 million people).^1,2 OA is a disabling chronic joint disease characterized by joint pain, tenderness, deformity, and functional impairment.^3,4 The strain, trauma and deformity of knee, hip and other weight-bearing joints can cause cartilage damage and bone hyperplasia, leading to the occurrence of OA.^5,6 The incidence rate is increasing year by year, which has seriously affected the life quality of OA patients and increased the heavy burden on social medical resources.^2,7 To date, no therapy has proved capable of halting or reversing OA. Management remains purely symptomatic—weight loss, tailored exercise, physiotherapy, and analgesics—until the joint is deemed beyond salvage. At that point, total joint replacement offers the only exit, but its steep price, intensive perioperative demands, and risk of complications weigh heavily on patients, families, and health-care systems.^8,9

While OA is traditionally framed as “wear-and-tear,” it is emergingly recognized as a whole-joint failure syndrome in which three inter-locking mechanisms—cellular senescence, metabolic homeostasis disorder and low-grade chronic inflammation—cooperate to dismantle cartilage, subchondral bone and synovial integrity.^10–12 Senescent chondrocytes (SnChos) and synovial cells release senescence-associated secretory phenotype (SASP) factors, including pro-inflammatory cytokines and matrix-degrading enzymes, which promote synovial inflammation and accelerate cartilage matrix breakdown.¹³ Inflammatory mediators such as IL-1β and TNF-α further induce stress responses in chondrocytes, increase oxidative stress, and promote additional cellular senescence, thereby linking inflammation to aging-related cell dysfunction.^14,15 At the same time, metabolic disturbances, particularly mitochondrial dysfunction and reactive oxygen species (ROS) imbalance, enhance cartilage catabolism and increase tissue sensitivity to inflammatory signaling.^16,17 Systemic metabolic factors, including obesity-associated adipokines and chronic low-grade inflammation, also contribute to sustained inflammatory activation within the joint and impair tissue repair capacity.^18,19 As a result, damage extends beyond cartilage to involve the synovium and subchondral bone, supporting the concept of OA as a whole-joint failure syndrome rather than a disorder confined to a single tissue.²⁰

Traditional treatment approaches, including non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief and joint replacement surgeries for advanced cases, have limitations.^3,21 NSAIDs may cause gastrointestinal and cardiovascular side effects,²² while surgical interventions are invasive and associated with risks such as infection and prosthesis failure.²¹ To overcome these limitations, there is an urgent need for innovative drug delivery platforms in clinical OA management.²³ In recent years, advanced nanoparticle-based delivery systems—such as liposomes, polymer vesicles, solid lipid nanoparticles, dendrimers, and hybrid nanocarriers—have been developed to enhance drug penetration into cartilage and prolong drug retention within the joint cavity.^24–28 These novel nano-delivery systems distinguished by their cartilage-penetrating dimensions and tailorable surface chemistry, showing promising potential in improving intra-articular drug targeting, extending therapeutic duration, and enabling stimulus-responsive precision delivery.^25,27 Due to their excellent biocompatibility, biodegradability, and environment-responsive cargo release properties, these nano-systems allow for localized, controlled drug delivery at OA-affected sites, offering strong translational prospects for future clinical applications.^24–28 Alternative biological approaches, particularly intra-articular mesenchymal stromal cell (MSC) therapies, have shown variable efficacy in pain reduction and functional improvement.²⁹ However, widespread adoption is constrained by inconsistent outcomes across cell sources and protocols, batch-to-batch variability, and complex regulatory hurdles.^30,31 Nanomaterial-based systems circumvent these limitations by offering superior controllability—enabling precise drug loading, cartilage-targeted surface modification, and prolonged intra-articular retention—thereby presenting a more readily translatable strategy for OA management.²⁶

Despite the burgeoning development of nanomaterial-based interventions, a fundamental understanding of how nanotherapeutic strategies engage with and modulate OA pathogenic mechanisms remains incompletely elucidated. In this review, we critically synthesize recent advances in rationally engineered nanotherapeutics targeting key pathogenic mechanisms of OA: cellular senescence, metabolic dysregulation, and immune-mediated inflammation (Figure 1). First, we dissected nano-enabled strategies for senescent cell clearance and quiescence, encompassing targeted delivery of senolytics and senomorphic nucleic acids, mitochondrial quality control, and SASP neutralization. Subsequently, we examined metabolic reprogramming approaches, including ROS scavenging, iron chelation, ferroptosis inhibition, and restoration of mitochondrial bioenergetics. Furthermore, we deliberate on immunomodulatory nanotherapeutic strategies centered on macrophage M1-to-M2 repolarization and pro-inflammatory cytokine neutralization. By delineating the molecular mechanisms underpinning these interventions, critically evaluating cartilage-specific delivery strategies, and identifying translational bottlenecks, we outline a roadmap for next-generation “disease-modifying nanomedicines”—therapeutic platforms that promise not merely to decelerate OA progression but to restore the biological clock of the joint.

Figure 1 Schematic illustration of recent advances in nanotherapeutic strategies for osteoarthritis targeting aging, metabolism, and inflammation. The diagram presents an integrated framework connecting pathological targets, core nanomaterial platforms, and mechanism-specific therapeutic effects across three interconnected disease mechanisms.

Nanotherapeutic Strategies Targeting Aging Pathogenesis in OA

OA is the most common joint disease in the middle-aged and elderly population.³² Emerging researches indicate that the mechanisms underlying the pathogenesis of OA are multifaceted, with aging being a key factor in promoting OA progression.^33,34 The aging mechanism of OA is due to factors involved in stress induction of chondrocytes,³⁵ telomere shortening,³⁶ DNA damage^37,38 and epigenetic changes.³⁹ Since aging-associated targets in OA are spatially confined within the dense, negatively charged cartilage extracellular matrix (ECM) and are exposed to rapid synovial clearance, conventional drugs often show limited penetration, poor retention, and insufficient cell specificity.⁴⁰ In this context, nanomaterial-based platforms can be engineered for cartilage-targeted binding, deep tissue penetration, and microenvironment-responsive release, thereby improving local bioavailability and enabling precise delivery of senotherapeutics or pro-regenerative cues.⁴¹ Therefore, exploring the aging mechanism of OA and potential nanotherapeutic strategies targeting aging will bring new possibilities for prospective treatment options for OA.^42,43

Nanotherapeutic Strategies Preventing Cellular Senescence

Cellular senescence, a core hallmark of aging, is typically triggered by persistent stress signals, including DNA damage, telomere attrition, oxidative stress, and mitochondrial dysfunction.⁴⁴ These triggers activate checkpoint pathways, primarily the p53/p21 and p16^INK4a/Rb axes, locking cells into stable cell-cycle arrest.^10,45 Concurrently, senescent cells undergo profound metabolic and phenotypic remodeling, developing a senescence-associated secretory phenotype (SASP) characterized by the release of pro-inflammatory cytokines (IL-6, IL-8), chemokines, and matrix-degrading enzymes (MMPs, ADAMTSs).^10,45 In OA, these aging-related processes prominently manifest in articular chondrocytes. During aging and disease progression, chondrocytes progressively acquire a senescent phenotype characterized by diminished anabolic capacity, heightened catabolic activity, and increased inflammatory output, thereby disrupting cartilage homeostasis and accelerating degeneration.⁴⁶ Therapeutic strategies targeting senescence include senolytics to selectively remove senescent cells, as well as NAD⁺-boosting agents and mitophagy inducers.⁴⁷ Senolytics are agents that selectively eliminate senescent cells by exploiting their apoptotic vulnerabilities, thereby removing the source of SASP factors and creating space for tissue regeneration. Conversely, senomorphics suppress or reprogram the harmful SASP without necessarily killing the cells, targeting upstream signaling pathways (JAK/STAT, mTOR, MAPK, NF-κB) that drive inflammatory and catabolic secretions.^48–50 Nanomaterial-based delivery systems provide a versatile platform to implement these strategies in OA because they can enhance cartilage retention, improve penetration through the dense extracellular matrix, and enable cell- or microenvironment-responsive delivery, potentially increasing efficacy while limiting off-target exposure.^41,43 Below, we systematically review nano-enabled senolytic approaches that directly remove SnChos, followed by nanotherapeutic senomorphic strategies that modulate SASP as well as inflammatory signaling and other novel strategies.

The pioneering work by Jeon et al established that selective clearance of SnChos in mouse models reduced histologic OA severity, improved pain behavior, decreased MMP-13 expression, and potentially stimulated cartilage regeneration.⁵¹ Building on this foundation, nanomaterial-based senolytic delivery has emerged as a promising approach to eliminate SnChos while sparing healthy chondrocytes.⁵² Efferocytosis, an intrinsic regulatory mechanism to eliminate apoptotic cells, will be suppressed due to the delayed apoptosis process in aging-related diseases.⁵³ However, the further efferocytosis effect and the secondary alteration of tissue homeostasis are always ignored, especially in the in situ degenerative lesion. Based on this, Xiong et al⁵⁴ engineered an innovative in situ senolytic platform termed A-Lipo/PAHM — aldehyde/methacrylic-anhydride modified hyaluronic acid microspheres prepared by micro-fluidic photo-cross-linking. After Schiff-base anchoring to collagen-II fragments within the degraded cartilage surface, the spheres release ABT263-loaded liposomes plus PDGF-BB; the former drives senescent-cell apoptosis, while the latter recruits surrounding MSCs. In-situ efferocytosis converts neighboring macrophages to a pro-resolving phenotype, halving p16^INK4a abundance and restoring glycosaminoglycan (GAG) content in an anterior cruciate ligament transection (ACLT) porcine cartilage explant OA model.

Enzyme-like Cu-based nanoparticles would favor the elimination of SnChos. Moreover, several previous studies indicate that Cu-based materials can promote MSCs chondrogenesis and cartilage repair.^55,56 Hence, Cu-based nanomaterials promote a chondrogenic microenvironment in articular cartilage after the clearance of SnChos. Wang et al⁵⁷ developed antibody-functionalized copper sulfide nanoparticles (B2M-CuS NPs) that target senescent chondrocytes via anti-β2-microglobulin (B2M) antibodies, a surface marker upregulated in cellular senescence. These nanoparticles exhibit peroxidase-like activity, converting endogenous H₂O₂ into toxic hydroxyl radicals (•OH) specifically within SnChos, inducing selective apoptosis while showing no toxicity to normal chondrocytes. Notably, Cu²⁺ released from the nanoparticles further promotes the chondrogenesis of surviving normal chondrocytes, creating a pro-regenerative microenvironment following senolytic clearance. Intra-articular injection into surgery-induced OA mice demonstrated effective cartilage regeneration.⁵⁷ However, long-term safety concerns regarding copper accumulation in subchondral bone and potential systemic ion release necessitate comprehensive biosafety evaluation.

Besides, recent advances in extracellular vesicle engineering have enabled RNA interference-based senolytic strategies.⁵⁸ In this regard, versatile engineered WPD-sEVssiMDM2 are loaded with siRNA targeting mouse double minute 2 homologue (siMDM2) and decorated with cartilage-targeting peptide WYRGRL-PEG2K-DSPE (WPD). This multifunctional modification enhances cellular uptake, cartilage penetration, and joint retention. By silencing MDM2, a negative regulator of p53, the system reactivates p53-driven apoptotic pathways specifically in SnChos, effectively eliminating senescent cells via the MDM2-p53 axis. The nanoplatform restored matrix homeostasis in OA and aged mouse models and reduced senescence in human explants⁵⁹ (Figure 2A).

Figure 2 Nanotherapeutic strategies preventing cellular senescence. (A) Schematic illustration showing the construction process of and mechanism of multifunctionally engineered WPD-sEVssiMDM2 with enhanced cartilage penetration ability and targeted senescent chondrocytes elimination effect for OA treatment. Intra-articular injection of WPD-sEVssiMDM2 successfully reduced the percentage of senescent chondrocytes, inhibited SASP factors production, and retarded cartilage degeneration in OA mice. Reproduced from Feng et al59 Copyright 2025, Wiley. (B) Schematic illustration of the BS@MD preparation and intra-articular injection for OA treatment by SASP neutralization and senescent chondrocytes elimination. Reproduced from Peng et al60 Copyright 2026, Elsevier. (C) Schematic illustration of locoregional generation of Klotho protein to mitigate OA. (a) Chemical structure of the NPs featuring a nuclear localization sequence (NLS) peptide as the hydrophilic moiety and stearic acid (SA) as the hydrophobic domain. (b) Schematic illustration of the preparation of plasmid DNA (pDNA)-laden peptide NPs (pPNPs). (c) Schematic illustration of the pPNP coating on hydrogel. (d) The pPNP-gel generates Klotho protein to ameliorate the aging microenvironment and delay arthritis progression. In the anterior cruciate ligament transection (ACLT) rat model, this approach ameliorates arthritis and promotes osteogenesis. Reproduced from Wang et al61 Copyright 2024, Springer Nature.

While senolytics remove senescent cells, senomorphics offer an alternative model: suppressing the deleterious SASP without eliminating the cells, thereby preserving any beneficial functions senescent cells may retain while neutralizing their inflammatory and catabolic output.⁴⁸ Yang et al⁶² synthesized copper-silicate nanoparticles loaded with astragaloside-IV (CSP@AS-IV) that exploit the mildly acidic synovial milieu of inflamed OA joints. The particle lattice dissolves in response to acidic pH, enabling tandem release of Cu²⁺ and AS-IV. Cu²⁺ provides antioxidant and anti-inflammatory signals, whereas AS-IV suppresses MMP13 and upregulates Col-II, collectively shifting cartilage metabolism toward matrix synthesis. Nevertheless, pH-triggered dissolution introduces sensitivity to lesion heterogeneity; acidity variations across synovial fluid, cartilage regions, and disease stages may cause inconsistent dissolution kinetics, underscoring the need for optimized microenvironment-responsive designs.⁶²

While endogenous cue–responsive nanosystems (eg, pH-triggered dissolution) offer energy-free release, their performance can be limited by lesion heterogeneity and insufficient “on demand” controllability.⁶³ To achieve tighter spatiotemporal control beyond endogenous cues, some nanoplatforms incorporate externally triggered release using near-infrared (NIR) light, which can be delivered noninvasively and provides rapid, switch-like activation at the illuminated site. In this regard, Xu et al⁶⁴ introduced an NIR-sensitive multifunctional heterostructure: EGCG (epigallocatechin gallate)-decorated Au–Ag nano-jars (E@Au–Ag). NIR activation enables on-demand release at the target joint, reducing reliance on repeated intra-articular injections. However, potential thermal effects on superficial collagen structures require careful optimization of irradiation parameters to balance responsive release with tissue safety.⁶⁴ Complementing this approach, Shi et al⁶⁵ engineered molybdenum nanodots (MNDs) that act as broad-spectrum scavengers of ROS and reactive nitrogen species (RNS) at physiological temperature, while generating mild photothermal heating upon 808 nm NIR irradiation. This dual mechanism restored mitochondrial fusion proteins, downregulated fission proteins, and reversed chondrocyte senescence.⁶⁵

Recognizing that senolytics and senomorphics may act synergistically, Peng et al developed a dual-engineered macrophage membrane-camouflaged nanoplatform (BS@MD) that combines both modalities⁶⁰ (Figure 2B). The system acts as a “nanosponge” to broadly neutralize heterogeneous SASP components while simultaneously delivering senolytic cargo. Anti-DPP4 surface conjugation enables selective targeting of SnChos, releasing bortezomib and sabutoclax to synergistically inhibit the NF-κB and BCL-2 pathways, thereby inducing SnChos apoptosis and suppressing SASP production. This dual mechanism effectively disrupts the senescence-inflammation feedback loop, addressing limitations of therapies that lack cell-specific targeting or fail to neutralize diverse SASP factors.

Nicotinamide adenine dinucleotide (NAD⁺) serves as an essential metabolic cofactor whose age-dependent decline accelerates cellular senescence and inflammation.^66–68 While NAD⁺ supplementation can reverse aging indicators and modulate macrophage polarization, its anionic nature and membrane impermeability necessitate high-dose systemic administration, and intra-articular delivery is hindered by ECM penetration resistance and rapid lymphatic clearance.⁶⁹ To overcome these barriers, Lin et al⁷⁰ developed injectable, self-lubricating hydrogel microspheres (NAD@NPs@HM) that continuously release NAD⁺ to simultaneously block chondrocyte senescence and repolarize synovial macrophages. Photo-cross-linked chondroitin-sulfate beads encapsulating lactoferrin-modified NAD-liposomes extend intra-articular residence while converting sliding friction into rolling friction. Single-injection treatment suppressed Src-driven glycolysis and shifted M1-to-M2 macrophages, interrupting the senescence-inflammation loop in aged mice.⁷⁰

The Klotho protein, an essential component of endocrine fibroblast growth factor (FGF) receptor complexes,^71–73 is a potent anti-aging factor downregulated in OA joints, suppressing chondrocyte catabolism via ZIP8 and MMP13 inhibition.^74–76 Tanshinone IIA (TIIA) complements this by inhibiting cellular communication network factor 1 (CCN1)-driven chondrocyte cluster formation and senescence.^77,78 Wang et al⁶¹ capitalized on this mechanistic synergy by engineering pPNP+TIIA@PFS—a stem cell-homing nanohydrogel that co-delivers Klotho plasmid and TIIA to achieve tripartite action: nuclear-targeted gene expression, dual-compartment ROS scavenging, and endogenous MSC recruitment (Figure 2C). Single intra-articular injection in ACLT rats elevated Klotho, suppressed catabolic markers ZIP8 and MMP13, alongside reduced osteophyte volume.⁶¹ However, optimization of formulation parameters and long-term safety profiling are warranted for clinical translation.

In conclusion, emerging nanotherapeutic designs that engage apoptotic clearance, exploit pathological microenvironment cues, or enable light-triggered on-demand release broaden the therapeutic toolbox for senescence-targeted OA beyond direct SASP suppression. Senolytic nanoplatforms offer the advantage of permanently removing deleterious cell populations, while senomorphic strategies provide a reversible, potentially safer alternative for chronic management. Moving toward clinical translation will require improving robustness across heterogeneous lesions and disease stages, defining safe and practical treatment regimens, and clarifying long-term biosafety issues such as ion retention and cumulative tissue exposure through rigorous in vivo and real-world evaluations.

Nanotherapeutic Strategies Regulating Autophagic Homeostasis

Emerging evidence underscores that defective autophagy, an evolutionarily conserved intracellular degradation system essential for maintaining cellular homeostasis, serves as a critical pathogenic driver in joint aging and OA progression.^79,80 During OA pathogenesis, compromised autophagic flux results in the accumulation of damaged organelles and misfolded proteins, thereby exacerbating chondrocyte dysfunction, accelerating cartilage matrix degradation, and ultimately promoting cell death.⁸¹ Central to this pathological cascade, the forkhead box O (FoxO) transcription factor, especially FoxO1 and FoxO3, emerge as pivotal regulators of cartilage homeostasis and autophagic activity.^82,83 Consequently, recent nanotherapeutic strategies have shown considerable promise in modulating autophagic homeostasis to enhance chondrocyte survival and attenuate inflammatory responses.⁸⁴ Specifically, nanomaterial-based delivery systems targeting FoxO represent an innovative therapeutic strategy, offering disease-modifying potential by restoring autophagic homeostasis and decelerating OA progression.⁸ For instance, Li et al⁸⁵ developed a CD90⁺ MCS-derived micro-vesicle (CD90@MV)-coated nanoparticle (CD90@NP). Poly (lactic-co-glycolic acid) (PLGA) nanoparticle was coated with CD90@MV, and a model glucocorticoid, triamcinolone acetonide (TA), was encapsulated in the CD90@NP (T-CD90@NP). T-CD90@NP promoted the regeneration of chondrocytes, reduced cellular senescence and apoptosis via the FOXO pathway, exhibiting significant chondroprotective effect in the rabbit and rat OA models. Besides, Feng et al delivered embryonic stem-cell-derived small extracellular vesicles (ESC-sEVs) that alleviate non-early-stage OA by rejuvenating SnChos. Notably, ESC-sEVs exert their anti-aging effects through activation of the FOXO1A-autophagy axis, without inducing apoptosis (Figure 3A). The approach attenuates OA progression in both mechanical-stress-induced and naturally aged mice models, and reverses the senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants.⁸⁶ However, the FOXO1A-autophagy axis is only one of several senescence-regulatory networks, and additional ESC-sEV–mediated pathways remain undefined. Moreover, weekly intra-articular administration is clinically impractical, necessitating the development of slow-release or depot-formulated ESC-sEVs.

Figure 3 Nanotherapeutic strategies in the regulation of autophagic homeostasis. (A) Schematic diagram of the harvest and application of ESC-sEVs for locally intra-articular injection in posttraumatic OA mice and naturally aged mice. Reproduced from Feng et al86 Copyright 2024, Elsevier. (B) Delivery of FGF18 using mRNA-LNP protects the cartilage against degeneration via alleviating chondrocyte senescence. Reproduced from Kong et al87 Copyright 2025, Springer Nature. (C) Schematic of FoxO3-NETT@SMs targeting-regulated Foxo3 gene in vivo to modulate mitochondrial dynamics for osteoarthritis therapy. Reproduced from Chen et al88 Copyright 2022, Elsevier.

Nanohydrogels or nanoparticles can be engineered to activate autophagy, primarily through the modulation of key regulatory signaling axes such as the mTOR/FOXO3a pathway.⁸⁹ These bioactive delivery systems not only function as vehicles for therapeutic cargo but also actively enhance local autophagic flux, thereby ameliorating age-related degenerative phenotypes at the tissue and organ levels. In this regard, Kong et al addressed the limitations of traditional protein delivery by developing an mRNA-LNP system for FGF18. The study explored a method that enables deeper cartilage penetration and sustained FGF18 expression, activating the FOXO3a-autophagy pathway to reduce chondrocyte senescence (Figure 3B). In both DMM and senile OA models, intra-articular injection LNP significantly alleviated OA symptoms by targeting autophagy and mitigating the aging phenotype.⁸⁷ Mitochondrial dynamics during mitosis are tightly coupled with selective macroautophagy (mitophagy).⁹⁰ This coordination between mitochondrial fission and autophagic activation maintains energy homeostasis, which is critical for cartilage integrity.⁹¹ Recent nanomaterials advances enable synergistic modulation of this axis for OA therapy. For example, biomaterials can be designed to activate mitophagy pathways selectively, such as the PINK1/Parkin pathway,⁹² which is responsible for recognizing and eliminating damaged mitochondria. These materials can selectively target mitochondria in chondrocytes or synovial cells, reducing oxidative stress and improving cellular function. One promising example is a study by Chen et al developing a FoxO3-NETT@SMs composite system centred on CRISPR/Cas9-based FOXO3 gene editing, delivered via the NETT nanocarrier and encapsulated within sodium alginate-hybridised exosome hydrogel microspheres (Figure 3C). The injectable nanoengineered hydrogel system can activate mitophagy via the PINK1/Parkin pathway, restore mitochondrial function, promote chondrocyte activity, and alleviate OA progression.⁸⁸ Therefore, autophagy-related transcription factors that regulates autophagy and mitophagy may suggest a promising point to explore aging-targeted materials for OA treatment. Through targeted regulation of these critical cellular processes, functional nanomaterials emerge as disease-modifying agents capable of mitigating aging-driven osteoarthritic changes, thus providing therapeutic avenues for treatment.

In conclusion, the application of nanotherapeutic strategies in regulating autophagic homeostasis has opened up an exciting new field for the treatment of OA and the improvement of joint health. Future real-world studies are needed to evaluate the additional benefits of autophagy-driven therapies in OA patients.

Nanotherapeutic Strategies Stimulating Cartilage Regeneration

During aging and OA progression, ECM alterations, including advanced glycation end-product accumulation, aggrecan degradation, reduced hydration, and collagen cleavage, progressively disrupt cartilage biomechanics and increase susceptibility to mechanical failure.⁹³ Because the ECM is continuously synthesized and maintained by chondrocytes, restoring the structural and functional integrity of cartilage matrix represents a critical therapeutic objective.¹⁰ However, the aged OA joint presents formidable delivery barriers: the dense, negatively charged cartilage ECM limits therapeutic penetration, while rapid synovial fluid turnover and lymphatic clearance compromise intra-articular retention.⁹⁴ Nanomaterial-based systems have been engineered to overcome these barriers by localizing pro-regenerative cues within cartilage, enabling sustained bioactivity and more efficient repair.⁹⁴ This section examines nanotherapeutic strategies for cartilage regeneration, mainly in the following aspects: (i) biomaterial-mediated structural reinforcement; (ii) stem cell and exosome-based regenerative platforms; and (iii) lubrication restoration and mechanics-senescence axis modulation.

Articular cartilage repair requires simultaneous satisfaction of stringent biomechanical requirements and support for cell-driven regeneration—a combination that conventional hydrogels often fail to achieve. To address the trade-off between mechanical stability and bioactivity, Zhou et al developed a dual physiological signal-responsive KPP@PLEL nanohydrogel. This system integrates a PAMAM dendrimer modified with MMP-13-responsive peptides and loaded with kartogenin (KGN), encapsulated within a thermosensitive PLEL hydrogel. By leveraging body-temperature gelation and MMP-13 responsiveness, KPP@PLEL enables sustained release and improved deep cartilage matrix penetration while extending joint residence. The platform demonstrated reduced inflammation, promoted bone marrow-derived mesenchymal stem/stromal cell (BMSC) chondrogenic differentiation, and enhanced cartilage regeneration with attenuated OA progression compared to free KGN or hydrogel alone.⁹⁵ Complementing synthetic approaches, bioinspired nanocomposites offer superior biomimicry. An injectable nanocomposite hydrogel incorporating 2% silk fibroin nanofibers and glucosamine into a thiolated chitosan matrix achieved in situ gelation following injection. Compared with pristine chitosan hydrogel, this formulation markedly improved compressive mechanical performance while enhancing cellular responses, including proliferation, migration, and chondrogenic differentiation. In a rat osteochondral defect model, the hydrogel promoted seamless tissue integration and articular surface restoration, accompanied by significant upregulation of cartilage markers COL-II and SOX-9.⁹⁶ These studies illustrate that nanoscale material design can simultaneously address the mechanical and biological requirements for functional cartilage repair.

Stem cell exhaustion is recognized as a hallmark of aging, reflecting the progressive loss of stem cell number and function and consequent decline in tissue repair capacity.⁹⁷ In aging-driven OA, this concept provides two practical therapeutic directions: reactivating endogenous stem cells within the joint or replacing impaired repair capacity through cell-based therapy. Mesenchymal stem cells (MSCs) have been widely explored for cartilage repair.⁹⁸ More recently, MSC-derived exosomes have attracted growing attention because they convey many of the anti-inflammatory and senescence-modulating benefits of MSCs while avoiding limitations of live-cell transplantation, including immunogenicity, tumorigenicity risk, and complex regulatory requirements.⁹⁹ However, a critical barrier is that SnChos accumulating in aged cartilage can undermine stem cell–mediated repair. Exposure to SnCho-conditioned environments induces BMSC apoptosis, suppresses proliferation, and impairs chondrogenic differentiation.¹⁰⁰ This suggests that effective regenerative delivery systems should not only provide pro-regenerative cues, but also mitigate the senescent microenvironment so that newly recruited or transplanted cells can survive and deposit healthy matrix.

Umbilical cord-MSC (UCMSC) exosomes offer particular advantages due to their multilineage differentiation potential, immunomodulatory properties, higher proliferation rates, and abundant supply without donor risk compared to adult MSCs.¹⁰¹ In this regard, Cao et al¹⁰² surface-engineered UCMSC-derived exosomes with a collagen-II-binding peptide and embedded them in thiolated hyaluronic acid microgels, creating a two-stage release system that rejuvenates aging chondrocytes in a rat OA model (Figure 4A). The collagen-binding peptide enables targeted delivery to cartilage, while the hydrogel matrix provides sustained release kinetics.

Figure 4 Nanotherapeutic strategies stimulating cartilage regeneration. (A) Preparation of the sustained-release of chondrocyte-targeting UCMSC-EXOs containing therapeutic miRNAs to rejuvenate OA chondrocytes in vivo. Reproduced from Cao et al102 Copyright 2023, American Chemical Society. (B) Schematic representation of Janus MGO nanoplatform preparation. (C) Schematic representation of the dual functions of Janus MGO nanoplatform. (D) Schematic representation of the dual-function principle of asymmetric MGO. (E) Schematic diagram of the mechanism by which MGO-FN alleviates cellular senescence, inhibits the secretion of inflammatory factors, and promotes matrix regeneration to restore lubrication. Reproduced from Chen et al103 Copyright 2026, Wiley.

Beyond exosome delivery alone, recent strategies integrate metabolic modulation with regenerative targeting. In OA cartilage, the CH25H–CYP7B1–RORα cholesterol axis has been reported to biases chondrocytes toward a SOX9-low, MMP13-high state, favoring matrix degradation over chondrogenic maintenance.¹⁰⁴ Zhao et al¹⁰⁵ suspended C5-24-peptide-labelled lipid nanoparticles (LNPs) in a self-assembling SKPPGTSS hydrogel to reset this cholesterol axis and recruit synovial MSCs for in-situ differentiation in ACLT rats. This approach demonstrates that metabolic reprogramming can remove molecular brakes on regeneration.

To address the poor cartilage-homing of injected MSCs, Wu et al¹⁰⁶ developed a nanoparticle-peptide dual-engineering strategy by electrostatically loading CuO@MSN with Sox9 plasmid (chondrogenesis driver) and Bmp7 protein (anti-hypertrophy factor), then click-conjugating peptide W that binds exposed Col2a1 fragments. The resulting W-CSB-MSCs enhanced hyaline cartilage matrix formation (Col2a1, Acan) while inhibiting hypertrophic differentiation in a surgically induced OA mouse model.¹⁰⁶ This illustrates how nanomaterial engineering can simultaneously improve cell targeting, control differentiation trajectories, and prevent undesirable phenotypic outcomes.

Age-related changes in the cartilage surface microenvironment can initiate a “mechanics-to-inflammation” cascade that accelerates degeneration. Aged cartilage is often associated with reduced lubricin proteoglycan 4 (PRG4), which increases boundary friction. The resulting mechanical stress exacerbates oxidative burden, promoting ROS accumulation and downstream activation of senescence-linked pathways including p53 signaling and iNOS-associated inflammatory responses.¹⁰⁷ Hou et al¹⁰⁸ addressed this mechanics–senescence feedback loop using microfluidic zwitterion-lubricated metformin microspheres (Met@SBHA). The formulation reduced the cartilage friction coefficient while enabling sustained metformin release and AMPK activation for up to 14 days, which was sufficient to improve mitochondrial membrane potential in aged rat knees.¹⁰⁸ This dual-action approach targets both the mechanical and metabolic drivers of chondrocyte senescence.

OA is sustained by a self-reinforcing cycle in which progressive cartilage surface wear compromises boundary lubrication, elevates frictional stress, and further accelerates matrix breakdown. Because most current interventions provide symptomatic relief rather than restoring lubrication or rebuilding surface integrity, their benefits are often transient, underscoring the need for regenerative and lubrication-restoring strategies that can break this cycle. Chen et al developed MGO-FN, an asymmetric nanoplatform that adheres to cartilage, provides lubrication, and releases the anti-aging drug fenofibrate. It effectively fills micro-damage, enabling sustained local treatment. Studies show MGO-FN reduces cartilage degradation, decreases inflammation, and restores lubrication, offering a multi-action therapy to halt OA progression¹⁰³ (Figure 4B–E).

In summary, current regenerative platforms increasingly prioritize restoring a permissive, low-senescence microenvironment so that recruited or delivered cells can survive, differentiate, and produce stable matrix. However, to translate these concepts into durable cartilage restoration, delivery systems must better match the kinetics of cartilage maturation by improving retention and release control while minimizing premature loss of bioactive cues. Future designs should integrate real-time monitoring capabilities to assess repair progression and enable personalized, adaptive therapeutic regimens.

Nanotherapeutic Strategies Targeting Promising Aging-Related Markers

Beyond the core senescence-clearance and autophagy-regulation strategies, emerging nanotherapeutic approaches are increasingly targeting specific aging-related molecular markers that govern cartilage homeostasis. These include the transforming growth factor-β (TGF-β) family, the NAD⁺-dependent deacetylase SIRT6, and the DNA damage response machinery centered on PARP1. These targets represent critical nodes where aging-associated dysregulation converges to drive OA pathology, offering precise intervention points for disease-modifying nanomedicine.

The TGF-β family, particularly TGF-β1 and TGF-β3, serves as a master regulator of chondrogenic differentiation, chondrocyte homeostasis, and directed cell migration through canonical SMAD2/3-dependent signaling.¹⁰⁹ However, exogenous TGF-β therapy is hindered by immunogenicity, rapid proteolytic clearance, poorly defined dose-response relationships, and prohibitive costs.^110,111 Notably, high-dose TGF-β may induce paradoxical synovitis, pannus formation, and cartilage erosion, underscoring the critical need for localized, controlled delivery.¹⁰⁹

Recent advances in nano-delivery engineering have sought to overcome these barriers through scaffold-mediated mechanical retention and cell-specific targeting. Starting from the cartilage surface, Zhou et al co-loaded TGF-β3 and kartogenin (KGN) into decorin-derived-peptide-decorated, inter-bilayer-cross-linked multilamellar liposomes. Inter-bilayer covalent bridging endows high shear tolerance in synovial fluid, while the decorin-mimetic peptide provides collagen II affinity, preferentially binding microfissured regions where collagen is exposed. This dual design promotes stable cartilage adhesion and sustained, localized release for nearly one month. In a full-thickness rabbit cartilage defect model, the construct improved defect filling and favored hyaline-like cartilage regeneration — a level of structural repair uncommon for freely diffusing nanoparticle formulations.¹¹² Mechanistically, the cross-linked lamellar scaffold concentrates TGF-β3 signaling at collagen II–positive lesion sites, limiting ectopic exposure and mitigating the hypertrophic tendency often observed with free TGF-β3 delivery.

In a complementary approach, Kim et al developed a hybrid system through ethanol-mediated fusion of TGF-β1-overexpressed extracellular vesicles with nicotinamide- and Col2A1-antibody-modified liposomes. The EV membrane protects TGF-β1 from uptake by synovial macrophages, while the liposomal shell delivers nicotinamide directly to macrophages, enabling dual-cell targeting within a single particle. This construct maintained cartilage homeostasis and prolonged intra-articular retention for up to one month in DMM rats, restricting TGF-β1 activity primarily to cartilage while reducing macrophage-associated activation.¹¹³ Both platforms achieve month-scale TGF-β retention, with cell-specific targeting toward collagen II or macrophages influencing whether the cytokine primarily promotes matrix synthesis or modulates immune responses. Future studies should focus on optimizing spatial and cell-specific regulation of TGF-β signaling to balance chondrogenic efficacy with immune homeostasis and facilitate clinical translation.

Sirtuins (SIRTs) are a family of NAD⁺-dependent deacetylases that play central roles in regulating cellular metabolism, genomic stability, and aging-associated processes.^114,115 SIRT6, in particular, has emerged as a key regulatory factor for age-related OA. Evidence indicates that SIRT6 deficiency exacerbates chondrocyte aging and OA progression through multiple mechanisms, including mitochondrial dysfunction, oxidative stress amplification, and inflammatory signaling.^116,117 Mechanistically, SIRT6 attenuates chondrocyte senescence by deacetylating STAT5 at conserved lysine 163, thereby blocking IL-15/JAK3-driven STAT5 nuclear translocation and dampening downstream pro-senescence signaling.¹¹⁶ Conversely, SIRT6 inhibition promotes a premature senescence phenotype marked by increased MMP-1/MMP-13, elevated p16^INK4a, aggravated DNA damage and mitochondrial dysfunction, and reduced expression of cartilage anabolic genes such as COL2A1 and IGF-1.^118,119

Despite the therapeutic potential, direct pharmacological targeting of SIRT6 in OA remains largely unexplored from a materials science perspective. The SIRT6-specific activator MDL-800 has exhibited SIRT6-dependent cellular effects in preclinical studies,¹²⁰ yet questions regarding its mechanism of action, optimal dosing, and long-term safety persist. Notably, no depot formulation currently embeds SIRT6 mRNA, the activator MDL-800, or NAD⁺-boosting precursors inside a cartilage-adherent carrier—representing a significant gap in the aging-targeted nanomaterials landscape. Liu et al¹²¹ reported that senescence-responsive miR-33-5p accelerates chondrocyte senescence and OA progression by targeting SIRT6, suggesting that antagomir-based strategies may offer an alternative route to enhance SIRT6 activity. In addition, miR-653-5p is upregulated under senescent conditions and counteracts chondrocyte senescence by promoting matrix synthesis and proliferation while suppressing IL-6/JAK1/STAT3 signaling, thereby attenuating senescence-associated phenotypes.^117,122 Therefore, the development of nanocarriers capable of delivering SIRT6-targeted miRNA modulators or small-molecule activators specifically to senescent chondrocytes represents a promising therapeutic frontier.

OA joint chondrocytes exhibit high levels of DNA damage, with elevated DNA damage markers identified in both elderly cadaver donors and end-stage OA samples,¹²³ suggesting that DNA damage-induced chondrocyte senescence represents a critical driver of OA progression.^37,38 Central to the DNA damage response is the NAD⁺-consuming enzyme poly-ADP-ribose polymerase 1 (PARP1). Upon detecting DNA strand breaks, PARP1 catalyzes the transfer of ADP-ribose units from NAD⁺ to target proteins, initiating DNA repair signaling and chromatin remodeling.^124,125 Persistent DNA damage in aging chondrocytes triggers PARP1 hyperactivation, leading to NAD⁺ depletion and subsequent mitochondrial dysfunction, thereby exacerbating cellular senescence and SASP propagation.^67,126 Recent evidence has revealed a more nuanced role of PARP1 in OA pathogenesis.¹²⁷ While excessive PARP1 activation can induce cell death through NAD⁺ depletion, regulated PARP1 activation may confer protective effects by reducing chondrocyte apoptosis and preserving cartilage integrity.^127,128 This dual nature suggests that modulation of the PARP1-NAD⁺ axis may be required for optimal therapeutic outcomes.

Beyond PARP1, the NAD⁺-degrading enzyme CD38 emerges as a critical regulator of NAD⁺ homeostasis in the aging joint. Inflammation and SASP accumulation promote CD38 expression on synovial macrophages, leading to NAD⁺ depletion and mitochondrial dysfunction through SIRT3 inhibition.¹²⁹ Despite these insights, nanotherapeutic strategies targeting the PARP1-CD38 axis remain unexplored. No current formulation delivers NAD⁺ precursors or CD38 inhibitors with cartilage-targeted, spatiotemporally controlled release. Developing nanoplatforms that simultaneously modulate PARP1 activity and inhibit CD38-mediated NAD⁺ degradation represents a critical unmet need for interrupting the DNA damage-senescence cascade in age-related OA. Table 1 summarized representative nanotherapeutic strategies targeting aging pathogenesis in OA.

Table 1 Representative Nanotherapeutic Strategies Targeting Aging Pathogenesis in OA

Nanotherapeutic Strategies Targeting Metabolism Pathogenesis in OA

In OA, metabolic homeostasis ensures chondrocyte viability via balanced metabolism. Reprogramming shifts energy production to glycolysis, causes mitochondrial dysfunction, disrupts lipid and amino acid metabolism, and drives cartilage degradation and disease progression.¹³⁰ Abnormal metabolism of cartilage is the key process in OA which attracted increasing interests in recent years.¹¹ ROS, which is one of the core characteristics of oxidative stress in OA, limits the self-repair ability of cartilage tissue by increasing catabolism and reducing anabolism, mediating the pathological progression of OA through multiple signaling pathways such as MAPKs, NF-κB and PI3K/Akt.¹³¹ Besides, recent studies highlight several other metabolic abnormalities that contribute to OA pathogenesis, including energy metabolism, chondrocyte survival, iron handling, angiogenesis, as well as mechano-chemical cartilage breakdown.¹³² Notably, emerging metabolic targets have also been identified as associated with OA and show therapeutic potential. Notably, nanotherapeutic strategies such as nanoparticle-based drug delivery systems enable targeted modulation of metabolic pathways in OA by enhancing drug retention, chondrocyte mitochondrial energy metabolism, and restoring metabolic balance.⁹⁴ Therefore, these promising strategies facilitate intra-articular targeting to address pathological metabolic alterations in OA.¹³³

Nanotherapeutic Strategies Targeting Oxidative Stress Caused by ROS

In OA, oxidative stress can disrupt the balance between anabolism and catabolism in joints,^134,135 which accelerates cartilage degeneration and hinders its repair mechanism.¹³⁶ Research has found that under the pathological condition of OA, the balance between antioxidants and ROS is disrupted,¹³⁷ which leads to oxidative stress and damage in chondrocytes, leading to cartilage degradation. Exogenous antioxidants, particularly superoxide dismutase (SOD), are a mainstream OA treatment.^138,139 Due to the inherent characteristics of SOD, that is, insufficient retention in disease sites and rapid inactivation of natural SOD, the pharmacokinetics, biodistribution and solubility of SOD can be significantly improved by nano-delivery.¹⁴⁰ Recent research highlights that nano-enzyme complexes with SOD-like activity offer superior catalytic antioxidant effects, chondroprotection properties, and enhanced in vivo stability and retention.^141–143 In this regard, Gui et al prepared a porous polymer vesicle with encapsulated SOD as antioxidant nanoparticles. The vesicle is composed of polyethylene glycol-polybutadiene copolymer (PEG-PBD) and polyethylene glycol-polypropylene oxide (PEG-PPO), which maintains good SOD activity, reduces its degradation, and enables ROS to enter the polymer, thus reducing the oxidative stress and damage of ROS to chondrocytes to treat OA.¹⁴⁴ Beyond the approach of directly neutralizing ROS with enzyme-based antioxidants, a recent novel strategy uses small interfering RNA (siRNA) delivery to modulate gene expression. Besides, Wu et al developed multifunctional nanoparticle platform TP/siMMP-13. TEMPO neutralizes ROS by mimicking SOD, while siMMP-13 silences catabolic gene expression, thereby suppressing cartilage degradation. Constructed from self-assembled 2,2,6,6-Tetramethylpiperidoxyl-polyethylene glycol-poly (lactic-co-glycolic acid) (TEMPO-PEG-PLGA) and cationic PEG-PLGA-OA9 polymers, it enables efficient intra-articular siRNA delivery to tackle oxidative stress and matrix degradation¹⁴⁵ (Figure 5A).

Figure 5 Nanotherapeutic strategies targeting oxidative stress caused by ROS. (A) Schematic illustration of the design of polymeric nanoparticles (TP/siMMP-13) for targeted osteoarthritis therapy through redox modulation and gene silencing. Reproduced from Wu et al145 Copyright 2026, Elsevier. (B) Schematic illustration of the synthesis and function of HA-SeNPs@AHAMA-HMs. Upon injection into the knee joint, HA-SeNPs@AHAMA-HMs exhibit cascade targeting functionality. The AHAMA-HMs selectively adhere to the surface of damaged cartilage through the formation of Schiff base bonds between aldehyde groups in their molecular framework and exposed amino groups on the cartilage surface, achieving micron-scale targeting. Subsequently, HA-SeNPs released from AHAMA-HMs bind to the highly expressed CD44 receptors on OA chondrocyte membranes via their HA shell, enabling nano-scale targeting. Once taken up by OA chondrocytes, HA-SeNPs establish a multifaceted antioxidant defense system by directly scavenging ROS and generating selenite to promote antioxidative selenoprotein synthesis. This effectively alleviates oxidative stress, optimizes mitochondrial function, and ultimately slows the progression of OA. Reproduced from Liu et al146 Copyright 2025, Elsevier. (C) Synthesis of TP/PTIO NPs. (D) Acid-responsive tea polyphenol nanoparticle-based hydrogel platform for osteoarthritis therapy through ROS/NF-κB and iNOS/NO/Caspase-3 signaling. Reproduced from Ding et al147 Copyright 2024, Elsevier.

In contrast to polymer-based siRNA delivery, the polymeric nanosystem enhanced cartilage penetration and retention.¹⁴⁸ For instance, Mei et al further developed multifunctional polymeric nanocapsules PDA@CBP-PTH, demonstrating superior ROS-scavenging capacity and significantly enhanced the anabolic activity of subchondral bone, contributing to improved joint microenvironment homeostasis in OA.¹⁴⁸ Small-molecule antioxidants help balance ROS but face biocompatibility issues, and converting them into macromolecular nanoscavengers often reduces activity. Recent study by Wang et al developed degradable nanoscavengers via dopamine and 4-formylphenylboronic acid polymerization, addressing the reduced efficacy of conventional macromolecular antioxidants. These degrade in acidic/ROS conditions, exposing groups to enhance antioxidation beyond monomersm, and alleviated oxidative stress and inflammation.¹⁴⁹ Additionally, selenium deficiency worsens OA by disrupting cartilage redox balance. To overcome the poor targeting of traditional supplements, Liu et al created a cascade-targeting system using selenium nanoparticles modified with hyaluronic acid (HA-SeNPs). These were loaded into special hydrogel microspheres that adhere to damaged cartilage. The system then targets OA cells via CD44 receptors, delivering selenium to combat oxidative stress and protect mitochondrial function¹⁴⁶ (Figure 5B).

Encouragingly, recent studies demostrated that introducing nanoparticles into the hydrogel can improve its mechanical strength, retention time, and ability to deliver antioxidants.¹⁵⁰ Nanoparticles can enhance hydrogel mechanics and enable sustained drug release, making hydrogel-nanoparticle composites a promising ROS-targeted OA treatment. Fan et al developed an injectable, boronate-based hydrogel loaded with icariin-PLGA nanoparticles. The system responds to OA’s acidic, high-ROS conditions for sustained drug release, aiming to reduce inflammation and promote cartilage repair, representing an advanced therapeutic strategy.¹⁵¹ Likewise, researchers developed a dual-action system combining tea polyphenol nanoparticles with a NO scavenger (carboxy-PTIO). This synergistic combination eradicates both ROS and NO, improving drug stability and enabling pH-responsive release at inflammation sites¹⁴⁷ (Figure 5C). Hence, this nanotherapeutic strategy shows promise for cartilage repair by reducing oxidative stress, and future research should focus on advanced constructs for better tissue integration.¹⁵²

Beyond particulate carriers, antioxidant scaffolds have been explored to improve cartilage regeneration and resist oxidative stress.^153,154 A PLLA/LP nanofiber scaffold was developed by grafting polylactic acid onto lignin, a phenolic polymer with antioxidant properties.¹⁵⁵ These were then fabricated into nanofibrous tissue engineering scaffolds using electrospinning. The resulting scaffolds were characterized for mechanical properties and antioxidant activity, aiming to support mesenchymal stem cell chondrogenesis for cartilage repair in an oxidative environment. This strategy enhanced the antioxidant capacity of lignin and promoted BMSCs to secrete GAG and upregulate the expression of COL2A1, ACAN, and SOX9 genes.¹⁵⁶ The utilization of nanofibre scaffolds endows desirable properties, including high surface area, biomimetic replication of native extracellular matrix structures, and tunable mechanical properties.^157,158 Therefore, this approach holds potential as a material targeting oxidative stress in OA metabolism.

Collectively, these nano-antioxidant systems not only provide amplified, long-lived ROS clearance but also integrate chondro-anabolic or osteo-anabolic cues, shifting the redox balance from injury to repair. By simultaneously scavenging ROS and safeguarding the ECM, nanotherapeutic strategies offer a versatile platform for interrupting the oxidative progression that underlies OA progression.

Nanotherapeutic Strategies Targeting ROS-Induced Changes in Cellular Behavior

Beyond direct oxidative damage, ROS can influence cellular behavior, such as osteoclast differentiation and chondrocyte apoptosis.¹⁵⁹ For instance, ROS promotes osteoclasts by acting as a second messenger in RANKL signaling and amplifying inflammaging, thereby activating NF-κB, MAPK pathways, enhancing differentiation and bone resorption. ROS inhibits osteoblasts differentiation through the GSK3β/β-catenin pathway, impairing oxidative phosphorylation (OXPHOS) and disrupting protein homeostasis, thereby exacerbating bone metabolic imbalance.^159,160 Additionally, ROS promotes the polarisation of M1 macrophages, thereby amplifying the inflammatory response and ROS production. Concurrently, it inhibits the polarization of M2 macrophages, exacerbating damage to joint tissues.¹⁶¹ ROS induces chondrocyte apoptosis and pyroptosis by activating CASP1, NLRP3 inflammasome, and NF-κB/p38 MAPK pathways, while inhibiting ECM synthesis and promoting degradation.¹⁶² These effects form a vicious cycle of ROS accumulation, cell dysfunction, and OA progression. Recent nanomedicine research has revealed ROS-responsive nanosystems targeting ROS-induced changes in cellular behavior holds significant application potential.¹⁶³ Through ROS-cleavable moieties, the systems scavenge excess ROS and release drugs on-demand, which reverses ROS-induced cell senescence and apoptosis, inhibits inflammation, and suppresses osteoclast activation.^163,164

ROS are involved in the regulation of osteoclast differentiation,¹⁶⁵ and this dysregulation contributes to aberrant subchondral bone remodeling and chondrocyte apoptosis.^159,160 In this regard, nanotherapeutic strategies modulating targeting subchondral bone to balance osteoclasts and osteoblasts represents a promising efficient strategy.¹⁶⁶ The therapeutic potential of polydopamine nanoparticles in mitigating reactive ROS has garnered increasing interest. These nanoparticles exhibit strong ROS-scavenging capacity, effectively reducing damage associated with acute inflammation. In materials science, PEG and its derivatives are widely used for surface modification to enhance stability and biocompatibility.¹⁶⁷ Wu et al developed methoxypolyethylene glycol amine (mPEG-NH2) modified polydopamine nanoparticles (PDA-PEG NPs). The synthesized PDA-PEG nanoparticles can scavenge ROS both in and out of cells, enhance the antioxidant function of nanoparticles. Mechanistically, these nanoparticles inhibited RANKL-induced IκBα phosphorylation and degradation, leading to the suppression of NF-κB and JNK signaling pathways, thereby inhibiting osteoclast differentiation. These findings highlight the potential of PDA-PEG nanoparticles as a therapeutic strategy for conditions characterized by excessive osteoclast activity in OA¹⁶⁸ (Figure 6A). In addition to inhibiting the transcription factors of osteoclast formation, inhibiting the differentiation of endochondral cells into osteoclasts is also a therapeutic approach.¹⁶⁹ Mitochondrial ROS can initiate the differentiation of progenitor cells into osteoclasts. Scavenging ROS can inhibit this differentiation, though most antioxidants cannot effectively enter the cartilage due to steric hindrance.^170–172 It was found that selenium-doped carbon quantum dots (SCT) can penetrate the dense structure of cartilage and reach chondrocytes, subchondral bone and medulla through intra-articular injection, which can effectively inhibit ROS under oxygen stress.¹⁷³ Zuo et al designed and synthesized highly permeable nano-hydrogel microspheres (SCT-HA), which can prevent SCT from being cleared and metabolized by capillaries and lymphatic vessels in synovium The embedded selenium atoms neutralize mitochondrial ROS in macrophages, inhibiting osteoclast differentiation and protecting chondrocytes from apoptosis, thereby maintaining cartilage matrix balance. In vivo, the microspheres reduce osteoclastogenesis and H-type vessel invasion, key drivers of abnormal bone remodeling, alleviating subchondral cartilage degeneration¹⁷⁴ (Figure 6B). Therefore, the SCT system demonstrates potential as a nanotherapeutic strategy for OA by regulating chondro-bone metabolism.

Figure 6 Nanotherapeutic strategies targeting ROS-induced changes in cellular behavior. (A) Schematic illustration of PDA-PEG nanoparticles inhibiting osteoclastogenesis and angiogenesis in subchondral bone. Reproduced from Wu et al168 Copyright 2022, Springer Nature. (B) Schematic diagram illustrating the inhibition of abnormal subchondral bone remodeling by SCT-HA. SCT-HA inhibits the differentiation of monocyte macrophages into osteoclasts and PDGF-BB production to suppress the abnormal invasion of subchondral bone blood vessels in OA. By inhibiting blood vessels, which act as the “executors” of abnormal bone remodeling, SCT-HA also prevents the occurrence of abnormal bone remodeling in subchondral bone. Reproduced from Zuo et al174 Copyright 2025, Wiley. (C) Schematic diagram of preparation and regulation of the “mitochondrial inspector”. (a) electrostatic self-assembly of PMNP. (b) The synthesis of RSRP by incorporation of dynamic diselenide bonds. (c) The injection of “mitochondrial inspector” for treatment of osteoarthritis by mitochondrial quality control. Reproduced from Chen et al175 Copyright 2025, Wiley. (D) Schematic illustration of the genetically engineered chondrocyte-mimetic HKL-GECM@MPNPs attenuating OA cartilage degeneration. Reproduced from Deng et al176 Copyright 2025, American Association for the Advancement of Science.

In chondrocytes, excessive ROS also disrupt mitochondrial function and cellular metabolism, ultimately promoting apoptosis and accelerating OA progression.¹⁷⁷ Recent advances in mitochondrial-targeted nanotherapies have demonstrated that restoring mitochondrial homeostasis is an effective strategy to counteract ROS-mediated cartilage degeneration.^17,178 Accumulating evidence suggests that disruption of mitochondrial quality control (MQC) homeostasis plays a critical role in cartilage degradation during the onset and progression of OA.¹⁷⁹ In this regard, Chen et al proposed cerium dioxide–based nanoplatforms, which enhance mitochondrial quality control to maintain chondrocyte stability under oxidative stress. Constructed with cerium dioxide nanozymes and metformin, it scavenges ROS and activates autophagy to clear dysfunctional mitochondria. By reducing cartilage degradation and osteophyte formation, this nanoplatform presents a novel subcellular therapy for aging-related OA diseases¹⁷⁵ (Figure 6C). Concurrently, a genetically engineered chondrocyte-mimetic nanoplatform (HKL-GECM@MPNPs) comprises a honokiol-loaded mitochondrion-targeting core encapsulated within an IL-1R2-overexpressing chondrocyte membrane. This design blocks IL-1β signaling via membrane-mediated receptor transfer and restores SIRT3 activity through mitochondrial HKL delivery, thereby protecting against inflammation-induced mitochondrial dysfunction in osteoarthritic chondrocytes¹⁷⁶ (Figure 6D). ROS-responsive nanoparticles further reprogram mitochondrial metabolism and direct macrophage polarization toward an anti-inflammatory phenotype.¹⁸⁰ In addition, Kumar et al combined manganese dioxide (MnO₂) with PEG to develop synthesized nanoparticles PEG-MnO₂, which is easily absorbed by cartilage and alleviates oxidative stress. MnO₂ catalyzes the breakdown of H₂O₂, the main ROS in chondrocytes, while PEG helps maintain nanoparticle stability. The nanoparticles can be used for cartilage penetration and long-term retention in joints, and can be located in cartilage in vivo, making it more targeted for the decomposition of ROS, thus reducing cartilage apoptosis.¹⁸¹ Besides, a targeted hydrogel delivering MnO₂ nanoparticles and NAD⁺ precursor to cartilage was developed recently. The nanoparticles catalyze oxygen generation while releasing NAD⁺, reactivating the mitochondrial respiratory chain. This dual approach reduces oxidative stress, improves NAD⁺/NADH balance, inhibits senescence signals, and protects cartilage, demonstrating a promising strategy to mitigate OA progression.¹⁸² Therefore, ROS-scavenging nanomaterials, which address the stability and bioavailability shortcomings of conventional antioxidants, are emerging as a promising therapeutic approach for OA.

Collectively, these studies establish that mitochondrial-centric, ROS-scavenging nanotherapies not only interrupt osteoclastic subchondral bone remodeling but also revive chondrocyte bioenergetics, thereby blocking the ROS-driven metabolic collapse that underpins cartilage degradation in OA.

Nanotherapeutic Strategies Targeting Energy Metabolism

Compared to healthy chondrocytes, OA chondrocytes showed increased extracellular acidification rate, more lactate production, and lower mitochondrial respiratory rates. These changes were accompanied by decreased cellular adenosine 5’-triphosphate (ATP) production, mitochondrial membrane potential and disrupted mitochondrial morphology.¹⁸³ Given this understanding, recent nanotherapeutic strategies have developed approaches targeting dysregulated energy metabolism, offering unique avenue to restore joint homeostasis.

Building upon the concept of restoring metabolic function, a novel nanotherapy was developed by conjugating mesenchymal stem cells with steroid-loaded gold nanostars (MSC-Au-Steroid). This strategy targets energy metabolism dysregulation in OA, normalizing inflammatory metabolic profiles such as glycolysis and oxidative phosphorylation, improving mitochondrial function, and suppressing ROS via mTOR regulation (Figure 7A). Therefore, MSC-Au-Steroid represents a promising disease-modifying agent targeting metabolic reprogramming.¹⁸⁴

Figure 7 Nanotherapeutic strategies targeting energy metabolism. (A) Nano-Steroid-Conjugated MSCs Target CD90⁺ chondrocytes via metabolic reprogramming for accelerated cartilage regeneration in osteoarthritis (OA). Reproduced from Lee et al184 Copyright 2026, Ivyspring International Publisher. (B) Oxygen nanopump (CZIF@Hb), composed of ZIF-8 and oxygenated Hb, was synthesized using a click chemistry approach. Upon intra-articular injection, CZIF@Hb specifically attached to and penetrated the chondrocyte membrane, releasing ZIF-8 and Hb in response to external ultrasound (US) stimulation and internal acidic conditions. This process effectively rebalanced the concentrations of O2 and CO2 within the microenvironment. Notably, the supplemental O2 and α-KG generated via the glutamine metabolic pathway enhanced TCA cycle activity and OXPHOS, thereby promoting hyaline cartilage formation and concomitantly alleviating OA. Reproduced from Xia et al185 Copyright 2025, American Chemical Society. (C) Schematic diagram of diselenide-linked self-assembly nanoprodrug for mitigating the inflammatory effect, facilitating cartilage functional regeneration, and potentially reversing disease progression in OA treatment. Reproduced from Li et al186 Copyright 2025, American Chemical Society. (D) Self-assembled microalgae extracellular vesicles/herb-based hydrogel for the treatment of OA; (a) Rhein (Rh) molecules can self-assemble into nanofibers via non-covalent interactions, which can further form a 3D bioactive Rhein hydrogel (Rh Gel) with the ability to encapsulate Spirulina platensis-derived extracelluar vesicles (SP-EVs); Eventually, the designed Rh Gel@SP-EVs integrate the therapeutic effects of both Rh and microalgae EVs; (b) In destabilization of the medial meniscus (DMM) surgery or monoiodoacetate (MIA)-induced mouse models, Rh Gel@SP-EVs effectively alleviate the OA progression by increasing ATP production, inhibiting catabolic metabolism, promoting anabolic metabolism, and suppressing inflammatory responses; (c) Rh Gel@SP-EVs exhibit excellent anti-inflammatory effects via the IL-6/JAK2/STAT3 signaling pathway, exerting regulatory effects on cytokine production and contributing to OA regression. Reproduced from Liang et al187 Copyright 2025, American Chemical Society.

The hypoxic microenvironment of cartilage restricts mitochondrial aerobic respiration, leading to insufficient ATP production and exacerbating energy metabolism defects, which in turn promote cartilage degeneration, subchondral bone sclerosis, and synovitis.^188,189 In this regard, a hemoglobin-loaded ZIF-8 nanopump (CZIF@Hb) has been engineered to deliver oxygen directly to the avascular cartilage, overcoming its hypoxic microenvironment. Triggered by passive (acidic microenvironment) and active stimuli (ultrasonic driving), CZIF@Hb disassembles with ZIF-8 adsorbs CO₂ and Hb releases O₂. By enhancing oxygen availability, this nanotherapy effectively fuels the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in OA chondrocytes, thereby boosting mitochondrial ATP production. CZIF@Hb activates a glutamate-mediated metabolic axis to boost energy synthesis, mitigating oxidative damage and synovial inflammation¹⁸⁵ (Figure 7B).

Furthermore, in addition to acid-triggered oxygen delivery, ROS-responsive nanotherapies have demonstrated application potential by leveraging distinct microenvironmental signals to restore energy homeostasis in OA joints.²⁵ The W/KGN@DSeD nanosystem, modified with WYRGRL peptide, is a cartilage-targeted and ROS-responsive nanoprodrug for OA therapy. In OA joints, the diselenide bonds in DSeD are cleaved, triggering the controlled release of diclofenac, kartogenin and selenium, which activates the Nrf2 pathway, promotes ECM synthesis for cartilage regeneration, and inhibits inflammation by suppressing PGE2. These components act synergistically to remodel the OA pathological microenvironment, achieving targeted and multimodal therapeutic effects with sustained joint retention and high biocompatibility¹⁸⁶ (Figure 7C).

Building on these stimuli-responsive platforms that modulate energy metabolism, recent work has explored a biohybrid hydrogel system combining naturally-derived vesicles with sustained release. Liang et al developed spirulina platensis-derived extracellular vesicles (SP-EVs) loaded into a pH-responsive rhein hydrogel (Rh Gel@SP-EVs), containing antioxidative and ATP-related compounds. This system enables sustained, intra-articular delivery of SP-EVs to chondrocytes. By improving oxidative stress, restoring mitochondrial membrane potential and ATP levels, and modulating the JAK-STAT3 pathway, Rh Gel@SP-EVs reduce inflammation, restore cellular energy homeostasis, and decelerate cartilage degeneration¹⁸⁷ (Figure 7D).

In summary, these novel nanotherapies target the energy metabolism in OA chondrocytes, achieving precise, spatiotemporal control over therapeutic delivery, and re-establishing metabolic equilibrium. The continued refinement of these intelligent, stimuli-responsive platforms holds significant promise for translating the concept of metabolic reprogramming into durable, disease-modifying clinical outcomes for OA patients.

Nanotherapeutic Strategies Targeting Novel Sites in Metabolism

Beyond classical antioxidant or anti-inflammatory strategies, nanotherapy is now targeting emerging metabolic nodes that govern chondrocyte survival, iron homeostasis, angiogenesis, and mechano-chemical cartilage breakdown. Leveraging superior colloidal stability, injectability, and cell uptake,⁵⁵ nanotherapies are being engineered to modulate mTORC1 signaling, ferroptosis pathways, VEGF receptors, and small-molecule chondro-inducers, offering multi-target collaborative strategies for OA management.

The mammalian target of rapamycin complex 1 (mTORC1) is abnormally activated in OA, which promotes chondrocyte hypertrophy, ECM degradation, and disrupts autophagy-apoptosis balance, inducing subchondral bone sclerosis and synovitis.^190,191 Inhibiting mTORC1 protects cartilage, reduces inflammation, and alleviates OA progression by restoring chondrocyte homeostasis.¹⁹² Rapamycin shows promise by targeting mTORC1 to mitigate OA progression, but its clinical application is hindered by poor water solubility, instability, and rapid clearance from joints. To overcome these limitations, Ma et al developed rapamycin-loaded PLGA nanoparticles (RNPs) with 85% entrapment efficiency. These RNPs achieved sustained intra-articular release, promoted chondrogenic differentiation, prevented chondrocyte senescence, and mitigated cartilage destruction, osteophyte formation, and synovitis in DMM mice.¹⁹³

Ferroptosis, driven by excess iron and oxidative lipid damage, has emerged as a key form of regulated cell death responsible for chondrocyte loss in OA.¹⁹⁴ Notably, downregulation of glutathione peroxidase 4 (Gpx4) in osteoarthritic cartilage heightens chondrocyte vulnerability to oxidative stress and drives ECM degradation, thus linking ferroptosis to OA progression.¹⁹⁴ To counter ferroptotic death, Li et al couple citric acid stabilized gold nanorods (Cit-AuNRs) with transient receptor potential vanillin 1 (TRPV1) monoclonal antibody (Cit-AuNRs@anti-TRPV1), and use AuNRs to intelligently target TRPV1 positive inflammatory macrophages and iron-laden chondrocytes to increase Gpx4 expression and inhibit chondrocyte iron prolapse to protect cartilage.¹⁹⁵

VEGF is upregulated in OA joints, with VEGFR2 mediating cartilage degeneration by promoting catabolic and hypertrophic gene expression and VEGFR1 driving pain transmission. Hence, inhibiting VEGFR1/2 relieves OA pain by blocking VEGFR1-mediated nociceptive signaling in DRG and spinal cord, and inhibits cartilage damage via VEGFR2 suppression, revealing VEGF’s novel role in OA neuropathic pain.¹⁹⁶ In this regard, Ma et al developed a nanoparticle formulation of pazopanib (Nano-PAZII) that markedly alleviated cartilage damage and joint pain in preclinical OA models.¹⁹⁷ Mechanistically, the improved nanoparticle can inhibit the phosphorylation activation of VEGFR2 in cartilage and VEGFR1 in synovium, reduce the expression of catabolic enzymes and inflammatory proteins in cartilage, and inhibit the development of knee OA and joint pain by nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signal pathway in knee joint and DRG sensory neurons.¹⁹⁷

In addition to the emerging targets mentioned above, numerous other novel metabolic targets for OA are being explored and identified. Promising nanomaterials, with their high specific surface area and facile surface modification, can serve as carriers to enhance drug accumulation and retention. Additionally, they can be applied in OA therapy by leveraging their unique properties, including catalytic activity, thermal conversion, and mechanical characteristics.¹⁹⁸ Conjugation to cartilage-homing carriers empowers small-molecule chondro-inducers to overcome the challenge of rapid clearance from intra-articular spaces, enabling deep penetration into the dense cartilage matrix.¹⁹⁹ To address their poor water solubility, inability to penetrate the dense avascular cartilage matrix, and rapid clearance from the joint, Xiong et al modified formononetin (FMN) by PEG and coupled cartilage-targeting peptides to prepare a specific cartilage-targeting nano-drug FMN-poly (ethylene glycol) (PCFMN)¹⁷¹. PCFMN can pass through cartilage and increase the duration of FMN, reduce inflammatory factors, reduce the upregulation of VEGF, reduce the expression of MMP-13, and significantly increase COL2al to protect cartilage.¹⁷¹ Similarly, He et al developed a multi-arm avidin (mAv) nano-construct that dramatically enhances intra-cartilage delivery efficiency Their earlier work established the ability of mAv to penetrate dense cartilage and transport small-molecule drugs into negatively charged avascular tissues,^200,201 and subsequently optimized the multi-arm avidin nano-construct for controlled intra-cartilage drug release.²⁰² Subsequently, He et al conjugated kartogenin (KGN) to mAv to create a cartilage-targeted therapeutic system MAV-KGN. Importantly, a single intra-cartilage administration of MAV-KGN markedly suppressed cytokine-induced OA-related catabolism and protected cartilage structure in vivo, representing a major advancement in cartilage-penetrating nanotherapies.²⁰³ In addition to targeting cartilage, recent studies have identified nanotherapeutic approaches targeting other parts of the OA joint such as synovium and subchondral bone. For instance, Ma et al developed MM@MT nanoparticles (MM@MT NPs) that regulate synovial mitochondrial metabolism for OA nanotherapy. Mechanistically, the system restores mitochondrial membrane potential and dynamics, enhance TCA cycle and OXPHOS, and boost antioxidant capacity, balancing ATP and ROS. By reprogramming synovial metabolism, MM@MT NPs remodel mitochondrial homeostasis, enabling symptomatic and etiological OA treatment.²⁰⁴ p16^INK4a expression is elevated in the synovium of OA patients. Park et al used PLGA nanoparticles to deliver p16^INK4a siRNA enabled targeted therapy to the synovium. This treatment reduced inflammatory cytokines in synoviocytes and catabolic factors in chondrocytes, alleviating pain and cartilage damage.²⁰⁵ Moreover, a dual-functional black phosphorus nanosheet (BPNS) therapy proposed by Lu et al targets both cartilage degradation and subchondral bone remodeling in OA. BPNSs scavenge ROS, restore chondrocyte homeostasis, and promote osteogenesis, showing excellent biocompatibility.²⁰⁶ Although current research on subchondral bone nanomaterials remains limited, it offers novel therapeutic options for future OA treatment.¹⁶⁶

In recent years, the development of stimulus-responsive intelligent nanoplatforms has emerged as a dynamic research direction in precision medicine, particularly for addressing the complex pathological microenvironment of OA.²⁰⁷ These systems are designed to exploit specific physiological cues — including localized pH shifts, elevated ROS, and dysregulated enzyme activities— to achieve controlled therapeutic intervention and enhanced imaging contrast.¹⁶⁶ The microenvironment-triggered systems not only prolong drug release but also improve tissue and cellular specificity, allowing more accurate modulation of catabolic mediators such as MMP-13.²⁰⁸ For example, pH-responsive nanotherapies act via acid-sensitive bond hydrolysis and chemical group protonation, triggering nanoparticle cracking to release bioactives.²⁰⁹ Yi et al developed pH-responsive lipid nanoparticles loaded with Urolithin A (LNPs@UA) as a smart nanoplatform targeting OA. By responding to the acidic synovial environment, LNPs@UA effectively deliver UA to inflamed joints, thereby reducing oxidative stress and inflammation, promoting M2 macrophage polarization, and protecting mitochondrial function.²¹⁰ The abundant ROS in the OA microenvironment, alongside pH changes, offers a key design principle for smart nanocarriers, as illustrated by ROS-responsive systems like the MgO-SiO₂ nano-capsules developed by Zheng et al²¹¹ Likewise, NO-responsive nanosensors developed by Jin et al can detect inflammation-associated NO elevations and selectively activate in diseased regions. Notably, MMP-13 expression is significantly upregulated as OA progresses, leading to further ECM degradation and exacerbation of the disease. This detrimental activity establishes MMP-13 as a critical biomarker and an attractive target for designing smart drug delivery systems for OA therapy.²¹² In this regard, an innovative smart nanoplatform (ERMs@siM13) targets early OA by responding to overexpressed MMP13. It features an MMP13-cleavable PEG shell with cRGD ligands and Cy5 fluorescence quenched by BHQ3. PEG detaches upon encountering MMP13, exposing cRGD to enhance chondrocyte uptake, delivering siM13 to silence MMP13. Concurrently, Cy5 fluorescence is restored, enabling real-time imaging of disease severity.²¹³ By integrating responsive motifs into material design, such systems enable spatiotemporally controlled diagnostic and therapeutic functions specifically within diseased tissues, thereby improving targeting accuracy while minimizing off-target effects.¹⁶⁶ This pathological characteristic-driven strategy holds significant promise for advancing the precision and efficacy of OA management.

Together, these findings underscore that nanotherapy-enabled metabolic reprogramming can simultaneously correct chondrocyte metabolism, protect matrix integrity and alleviate pain, opening new avenues for single-dose, multi-target disease-modifying therapy in OA. Table 2 summarized representative nanotherapeutic strategies targeting metabolism pathogenesis in OA.

Table 2 Representative Nanotherapeutic Strategies Targeting Metabolism Pathogenesis in OA

Nanotherapeutic Strategies Targeting Inflammation Pathogenesis in OA

OA is now widely recognized as a low-grade inflammatory disease that affects the entire joints, which is characterized by cartilage breakdown and synovial inflammation.^214,215 As a key marker and driving factor in the OA progression, inflammation plays a central role in its pathophysiology through its clear association with immune cells.¹² Immune cells play a crucial role in OA mainly such as macrophages, T cells, and NK cells.^190,216 In this regard, macrophages, as central immune regulators, coordinate anabolic and catabolic activities across diverse cell populations, thereby driving disease progression.²¹⁷ In addition to immune cells, inflammatory cytokines are among the critical mediators of OA pathophysiology.²¹⁸ Thus, nanotherapeutic strategies targeting macrophages polarization, immune cells function and inflammatory cytokines production become potential therapeutic options for the treatment of OA. For instance, further optimization of this capability can be achieved through precise control over their physicochemical attributes as well as incorporation into hydrogel networks, which enhances biocompatibility, minimizes nanoparticle aggregation, and facilitates injectability, thus supporting their tailored design for targeted therapeutic uses.^219–221 This section highlights recent nanomedicine approaches that specifically target immunoinflammation in OA.

Nanotherapeutic Strategies Reprogramming Macrophage Polarization

Emerging evidence underscoring the critical role of the polarization process of macrophages towards the M1 and M2 phenotypes, which drives synovitis, matrix degradation, and impaired tissue repair.²²² Modulating this polarization represents a promising therapeutic strategy, and recent advances in nanotherapeutic offer innovative solutions.²¹⁹ Nanomaterials with tunable physicochemical properties can effectively reprogram macrophages toward an M2-dominant phenotype both in vitro and in vivo. This shift reduces M1-associated inflammatory mediators while enhancing M2-linked anti-inflammatory factors, thereby attenuating synovitis, protecting cartilage, and slowing OA progression.²²⁰ Mechanistically, these effects are achieved via modulation of transcription factors, key intracellular, signaling pathways and environmental signals.²²³ By leveraging such pathway-specific immunomodulation, nanomaterials not only suppress the inflammatory microenvironment but also foster a regenerative milieu, positioning nanotherapeutic strategies as targeted and effective strategies for OA management.^219,220

Accordingly, nanotherapeutic approaches to directly eliminate M1 macrophages or inhibit M1 polarization, thus reducing the secretion of harmful cytokines may be potential treatments for OA. In this regard, Li et al developed GelMA@FPPD, folate-functionalized micelles encapsulating dexamethasone for M1 macrophage targeting via folate receptor β in OA (Figure 8A). This in situ targeting system leads to inhibition of cytokine storm, induction of M1 apoptosis, and downregulation of cytokines such as IL-1β and TNF-α. By mitigating synovial inflammation and protecting articular cartilage, GelMA@FPPD significantly attenuates OA progression in vivo.²²⁴ Besides, BRD4 is an epigenetic regulator that is highly expressed in OA cartilage and synovium, where it regulates macrophage polarization related signaling to promote inflammatory progression.²²⁵ Xu et al developed apoptosis-stimulated phosphatidylserine nanoliposomes loaded with the BRD4 inhibitor JQ1 (JQ1@PSLs), which specifically target synovial macrophages, inhibit M1 polarization, and thereby alleviate synovial inflammation and cartilage degradation in OA.²²⁶

Figure 8 Nanotherapeutic strategies reprogramming macrophage activation and polarization. (A) Schematic diagram of nanomicelle–hydrogel microspheres (GelMA@FPPD) that sustainably target and regulate M1 macrophage, inhibit “cytokine storm”, and alleviate OA. Reproduced from Li et al224 Copyright 2023, American Association for the Advancement of Science. (B) Schematic representation of the multifunctional therapeutic roles of mCNP-G through a “push-and-pull” action, involving (i) dual scavenging of ROS and cfDNA and (ii) delivery of an anti-inflammatory drug, as well as through (iii) high affinity for the cartilage matrix, enabling prolonged retention and tissue penetration. Reproduced from Singh et al227 Copyright 2025, American Chemical Society. (C) Preparation of G4-TBP NPs-FN for the combination treatment of OA via macrophage polarization, oxidative stress alleviation, and stem cell osteogenic differentiation. Reproduced from Zhan et al223 Copyright 2024, American Chemical Society. (D) Gel-PMPC evades synovial macrophage phagocytosis by inhibiting C3 adsorption. (a) C3 opsonization on conventional nano-lubricants initiates synovial macrophage phagocytosis within joint cavity, while Gel-PMPC can inhibit C3 opsonization on its surface. (b) Gel-PMPC evades synovial macrophage phagocytosis mediated by binding of C3 (on NPs) to CD11b (on synovial macrophages). (c) Excessive uptake of NPs by synovial macrophages leads to the harmful release of cytokines, inflammation, and progressive tissue injury, while Gel-PMPC maintains macrophage homeostasis by evading macrophage phagocytosis. Reproduced from Cai et al228 Copyright 2025, Wiley.

Pro-inflammatory molecules, such as excess ROS and cell-free DNA (cfDNA), are major influencing factors in OA, which require regulation through effective clearance mechanisms. A high level of cfDNA in the articular cavity would recruit and activate immune cells, ultimately promoting the onset and progression of OA.²²⁹ Besides, ROS drives OA via chondrocyte damage, synovitis aggravation and chondrocyte aging, forming vicious pathological cycles.²³⁰ Based on this, Shi et al created polyethylenimine (PEI)-functionalized diselenide-bridged mesoporous silica nanoparticles (MSN-PEI) with possessing high nucleic acid binding and antioxidative properties. MSN-PEI reduced cfDNA levels and oxidative stress in the joint cavity and suppressed M1 macrophage polarization during OA progression.²³¹ In contrast to MSN-PEI, which relies on PEI-mediated cfDNA binding and diselenide-based ROS responsiveness, Singh et al developed a multifunctional “push-and-pull” nanotherapeutic system integrating drug delivery with dual scavenging of ROS and cfDNA within a single mesoporous ceria platform, modulating macrophage polarization, and targeting cartilage to effectively alleviate OA in rat models.²²⁷ The mesoporous ceria (mCNP) core provides broad-spectrum ROS elimination, while the polycationic PAMAM-G3 shell binds cfDNA and boosts cartilage retention. Additionally, mesopores allow pH-responsive dexamethasone release for anti-inflammatory “push” alongside ROS/cfDNA “pull”. This integrated system suppresses macrophage activation, protects chondrocytes, enhances joint retention and penetration, and improves OA therapy²²⁷ (Figure 8B).

Multiple intracellular signaling pathways, including PI3K/Akt/mTOR, MAPK, NF-κB, JAK/STAT and hypoxia-dependent signaling, govern polarization between pro-inflammatory M1 and reparative M2 phenotypes.^190,232 In regulating NF-κB pathway, drug-loaded nanocarriers has gained increasing traction due to its combined antioxidant, metabolic-regulatory, and signal-modulatory properties.^233,234 In particular, Zhang et al designed core–shell quercetin nanoformulations with improved aqueous stability and prolonged synovial retention, enabling sustained intra-articular activity. Their system effectively scavenged excessive ROS, reduced expression of IL-1β and TNF-α, and reprogrammed synovial macrophages from M1 to M2, thereby reconstructing a pro-repair microenvironment rather than merely suppressing inflammation²³⁵ (Figure 9A–C). Sun et al further introduced G2-OH₂₄ phosphorus dendrimers co-delivering catalase (CAT) and quercetin. The co-delivery nanosystem strengthens 0069ntracellular antioxidant defense via upregulation of SOD and glutathione, while downregulating hypoxia-inducible factor (HIF-1α) and glycolysis-related proteins, promoting durable M2-skewed macrophage profiles and mitigating cartilage matrix loss in vivo.²³⁶ Building on these findings, Huang et al developed immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ), which targets M1 macrophages and disassembles under oxidative stress. Released bilirubin and JPH203 scavenge ROS and inhibit inflammatory pathways, repolarizing macrophages to an M2 state²³⁷ (Figure 9D). Collectively, these studies highlight nanosystems as versatile immunoregulatory scaffolds that reshape synovial immune homeostasis through integrated metabolic and transcriptional reprogramming. However, its intrinsic hydrophobicity, rapid clearance, and limited cartilage penetration necessitate optimized delivery platforms to achieve clinically actionable bioavailability and sustained therapeutic efficacy.

Figure 9 Drug loaded nanocarriers treat OA by modulating intracellular pathways and reprogramming macrophage polarization. (A) The preparation schematic diagram of CCM@ZIF-8@Que nanoparticles. (B) The structure diagram of MH/CSM@ZIF-8@Que hydrogel. (C) The mechanism of MH/CSM@ZIF-8@Que hydrogel promoting OA therapy. Reproduced from Zhang et al235 Copyright 2025, Wiley. (D) Schematic illustration of the preparation and mechanism of opsonized bilirubin/JPH203 nanoparticles (IgG/BRJ) for osteoarthritis therapy. Reproduced from Huang et al237 Copyright 2024, Wiley.

The hypoxic conditions within the joint can trigger an increase in HIF-1α expression, influencing the equilibrium of macrophage polarization. Modulating this hypoxic microenvironment emerges as a crucial strategy for enhancing OA interventions.¹⁶⁰ In this regard, Zhou et al synthesized encapsulated S-methylisothiourea hemisulfate salt (SMT) and CAT ZIF-8 NPs to restrain HIF-1α and recover macrophage mitochondrial dysfunction. The system relieves hypoxia by catalyzing H₂O₂ to O₂ and inhibiting NO production, suppresses HIF-1α, restores mitochondrial function, reprograms metabolism, and shifts synovial macrophages from M1 to M2.²³⁸ Chen et al developed opsonization-based macrophage-targeting IgG/Fe-CV nanoparticles incorporating Chrysin and V-9302.²³⁹ This nanosystem targets M1 macrophages via IgG opsonization, inhibits HIF-1α and GLUT1 to block aerobic glycolysis, suppresses glutamine uptake, thereby reprograming M1 to M2 polarization, relieves hypoxia, and alleviates OA inflammation and cartilage damage.²³⁹

To enhance the specificity of nanomedicines targeting active inflammation in nanotherapeutic strategies, targeting ligands like folic acid, cartilage-targeting peptides, chitosan and hyaluronic acid,^240,241 or biomimetic cell membrane coatings from macrophage, neutrophile and other immune cells, have been decorated on the surface of nanoparticles. Additionally, anti-inflammatory receptors and chemokine receptors on the membrane surface enable targeted inflammation, thereby mediating macrophage recruitment and reprogramming.²⁴² Protein-engineered nanoparticles can enhance the stability and therapeutic efficacy of intra-articular drug delivery.²⁴³ Due to M1/M2 synovial macrophages imbalance in OA pathophysiology, inhibiting aerobic glycolysis to promote the shift from M1 type to M2 type is a therapeutic strategy for OA. Macrophage-targeting IgG/Fe-CV nanoparticles were developed, which inhibited aerobic glycolysis and glutamine uptake in M1 macrophages, promoting their repolarization to the anti-inflammatory M2 phenotype.²³⁹ Besides, nanoparticles coated with fibronectin (FN) renders them to specifically target tumor cells to enhance the drug delivery efficiency.¹⁶⁶ To further enhance targeting specificity and immune microenvironment regulation in OA, Zhan et al developed ROS-responsive HOOC-PEG-TK-PLGA nanoparticles loaded with G4-TBP and subsequently modified their surface with FN. The G4-TBP NPs-FN nanosystem targets macrophage reprogramming via FN’s RGD binding to macrophage β1 integrin for specific uptake. ROS-responsive dissociation releases G4-TBP and FN, which scavenge ROS, alleviate hypoxia, inhibit NF-κB/PI3K/Akt pathways, suppress M1 markers, and protect macrophages from apoptosis, thus driving M2 polarization efficiently²²³ (Figure 8C). Recently, nanozyme provides novel strategies for OA treatment by scavenging ROS and improving intra-articular delivery and retention.²⁴⁴ An injectable hydrogel containing ε-PLE/MnCoO nanoparticles with catalase-mimicking nanozyme activity designed by Wang et al alleviates OA by scavenging ROS, polarizing M1 to M2 macrophages, reducing inflammation, and promoting cartilage repair.²⁴⁵

Cell membrane-camouflaged biomimetic nanovesicles merge cell membrane properties with drug delivery to overcome poor bone targeting. These nanoparticles enhance biocompatibility, prolong circulation, and improve targeted delivery. Functionalized membrane modifications enable more precise therapy, making them ideal for treating bone-related conditions.²⁴⁶ In this regard, Cai et al developed a biomimetic nanoparticle formulation coated with macrophage cell membrane-derived functional proteins, enabling the particles to avoid recognition and phagocytosis by pro-inflammatory M1 macrophages. This immune-shielded delivery system prevented excessive macrophage activation, reduced overproduction of TNF-α and IL-6, and stabilized the synovial immune microenvironment by limiting feed-forward inflammatory amplification. In OA rat models, the biomimetic nanoparticles significantly alleviated synovitis and cartilage degeneration, illustrating that restraining inflammatory activation at the macrophage–ECM interface is a viable strategy for halting OA progression²²⁸ (Figure 8D). Additionally, dual-engineered macrophage-membrane nanoplatform (BS@MD) enables NF-κB/BCL-2 blockade, while membrane receptors broadly neutralize SASP and promote M1 to M2 macrophage transition.⁶⁰ Moreover, Fu et al designed neutrophil membrane-coated nanoparticles loaded with siIL33 (NM-NP-siIL33). Based on the ability of IL-33 to induce chondrocyte senescence through p38 MAPK-mediated autophagy inhibition, NM-NP-siIL33 delivered siIL33 to OA tissues, thereby reducing cartilage degradation.²⁴⁷ In summary, protein-engineered and biomimetic nanoparticles offer a versatile platform for targeted OA therapy. By modulating the synovial immune microenvironment through metabolic reprogramming, ROS scavenging, or immune evasion, these systems effectively suppress inflammation and protect against cartilage degradation.

Recent studies have highlighted that the therapeutic effects of MSCs in OA are largely mediated through their secreted extracellular vesicles (EVs), which regulate synovial macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, thereby alleviating joint inflammation and cartilage degradation.²⁴⁸ For instance, hUCMSC-derived EVs have been shown to reduce m6A modification of NLRP3 mRNA by delivering miR-1208, which binds METTL3 and suppresses NLRP3 inflammasome activation. This pathway leads to decreased release of pro-inflammatory cytokines and reduced cartilage ECM degradation, thereby attenuating OA progression in vivo.²⁴⁹ Li et al discovered that extracellular vesicles from human umbilical cord mesenchymal stem cells (hUCMSC-EVs) may promote M2 macrophage polarization, exhibiting anti-inflammatory effects and immunomodulatory potential in OA progression by delivering key proteins and modulating miRNAs through the PI3K-Akt signaling pathway, thereby alleviating inflammation and cartilage degradation.²⁵⁰ EVs derived from BMSCs can alleviate cartilage damage, reduce osteophyte formation, and alleviate arthritis by inhibiting M1 macrophage production and promoting M2 macrophage production.²⁵¹ This shift from M1 to M2 macrophage predominance, documented in multiple independent studies including BMSC-EV animal models and MSC-EV immunomodulatory reviews, underpins the chondroprotective effect in OA.^252,253

Meanwhile, hydrogel-nanosheet combination therapies show great potential for OA treatment, exhibiting multi-target effects such as anti-inflammation, antioxidation, and cartilage regeneration, while also possessing high biocompatibility and minimally invasive delivery characteristics.²⁵⁴ For instance, Zhang et al developed an injectable hydrogel platform loaded with calcium boride nanosheets (CBN), CBN@GelDA hydrogel. It could continuously release H₂ in suit than CBN alone, inhibiting scavenge excessive ROS to repolarize macrophages from M1 to M2 as well as reducing inflammatory expression, thus alleviating OA progression.²⁵⁵ Additionally, Zhao et al designed an injectable chitosan-based hydrogel (L-MNS-CMDA) loaded with MnO₂ nanosheets. It offers mechanical support, tissue adhesion, scavenges H₂O₂ to relieve oxidative stress, and shifts macrophages from pro-inflammatory M1 to regenerative M2 phenotype, creating an immune-friendly environment. Consequently, it reduces early inflammation and significantly enhances cartilage regeneration and joint function in rat model, demonstrating strong clinical potential.²⁵⁶ Hence, hydrogel-nanosheet systems represent a promising and multifunctional strategy for OA therapy, enabling synergistic anti-inflammatory, antioxidant, and chondroprotective effects.²⁵⁷

In conclusion, the application of nanotherapeutic strategies in regulating macrophage polarization represents a promising and rapidly evolving approach for OA treatment. By modulating the synovial immune microenvironment via altering material properties such as surface modification of nanoparticles and hydrogel-nanosheet combination, these nanosystems effectively suppress inflammation and protect against cartilage degradation.

Nanotherapeutic Strategies Modulating Immune Cell Functions

Dysregulated activation of immune cells in the pathogenesis of OA causes spanning polarized phenotypes, metabolic reprogramming, and inflammatory cell death, promoting synovitis, cartilage degradation, and joint destruction.²⁵⁸ Modulating these multifaceted immune cell functions represents a promising therapeutic frontier, and recent advances in nanotherapeutics offer increasingly superior strategies to achieve this goal.²¹⁹ By leveraging biomimetic designs, metabolic interventions, and precision targeting, these nanotherapeutic strategies aim to convert pro-inflammatory immune cells from drivers of tissue destruction into promoters of resolution and repair.

M2 macrophages can secrete anti-inflammatory factors. However, they also present low-expression of some pro-inflammatory cytokines and induce cartilage damage by expressing some MMPs.²⁵⁹ On-demand M2 mimics have therefore been engineered. Ma et al developed artificial M2 macrophages (AM2M) composed of macrophage membrane as “shell” and inflammatory response nanogel as “yolk”. The nanogel was prepared by physical interaction between gelatin and chondroitin sulfate (ChS) through ionic and hydrogen bonds. ChS was used to simulate the beneficial secretion of M2 macrophages in OA therapy to improve the treatment of OA. Artificial M2 macrophages can reside in inflamed areas for a long time, downregulate inflammation, and are continuously released to repair cartilage when there is low inflammatory activity.²⁶⁰ Consistently, Tong et al exploited the same ChS-based NPs for the bioencapsulation of FGF18, which not only suppressed IL-1β–induced chondrocyte inflammation, but also promoted M2 macrophage polarization while inhibiting M1 activation, further emphasizing the therapeutic value of ChS-based immunomodulatory delivery systems in OA²⁶¹ (Figure 10A). Considering the potential uptake by macrophages and lack of targeting in the circulation by conventional drug delivery, Xue et al fused erythrocyte membranes and neutrophil membranes on a hollow copper sulfide surface to provide a promising platform (D-CuS@NR NPs) for inflammation-associated diseases. This biomimetic nanoparticle possesses excellent photothermal conversion capacity and controlled drug release behavior.²⁶²

Figure 10 Nanotherapeutic strategies modulating immune cell functions. (A) Schematic diagram demonstrating the construction and use of a bionic thermosensitive sustainable delivery system for remodeling the anti-inflammatory and immunomodulatory microenvironment in OA. Reproduced from Tong et al261 Copyright 2024, Wiley. (B) Schematic representation of LCF-CSBN targeting the Golgi apparatus in M1 macrophages and promoting M1 macrophages to M2 phenotype by reprogramming sphingolipid and arachidonic acid metabolism. Reproduced from Deng et al263 Copyright 2025, Wiley. (C and D) Photoactivatable exosenolytics activate natural killer cells for delaying osteoarthritis via activation of cGAS/STING pathways. (C) Schematic illustration of the design and biological function of exosenolytics (R-ESC@P). (D) Following intravenous injection, exosenolytics exhibit a remarkable ability to home in the synovitis site of OA joints, responding to elevated inflammatory factors in the OA microenvironment. Upon reaching the synovium, the aPD-L1 antibody is released through the cleavage of matrix metallopeptidase-9 (MMP-9), which is overexpressed in the OA synovial microenvironment. The remaining exosenolytics selectively accumulate in Sn-FLS by targeting integrin αvβ3, enabling real-time visualization of OA joints through in vivo imaging. Subsequent activation of photodynamic therapy (PDT) induces the recruitment of NK cells to the synovium. Exosenolytics enhance the gripping effect of NK cells on Sn-FLS by blocking the aPD-L1-PD-L1 immune checkpoint pathway, thereby preventing immune evasion of senescent cells. Additionally, the release of SB-3CT further activates NK cells by inhibiting the shedding of soluble NKG2D ligands, such as MICA and ULBP1, which are critical for NK cell recognition and targeting of senescent cells. Through these mechanisms, exosenolytics promote a cGAS-mediated inflammatory response in NK cells, enhancing their ability to eliminate senescent cells for delaying OA. Reproduced from Zhang et al264 Copyright 2025, American Chemical Society. (E) Intradermal injection of LNP-Col II-R to OA mice would induce Col II–specific Tregs. The Tregs in the synovium would inhibit M1 macrophages and TH1 cells, both of which express inflammatory cytokines (eg, TNF-α, IFN-γ, and IL-1β) and inhibit chondrocyte apoptosis and matrix destruction in the OA articular cartilage. Reproduced from Sohn et al265 Copyright 2022, American Association for the Advancement of Science.

Metabolic dysregulation drives low-grade inflammation in OA by coordinating inflammatory and redox pathways in macrophages.²¹⁶ The metabolism-inflammation crosstalk in chondrocytes also highlights metabolic modulators as promising therapeutic targets for OA.²⁶⁶ Based on the fact that lipid-metabolic rewiring can switch macrophage fate, Deng et al developed a self-assembling nanoparticle (LCF-CSBN) targeting M1 macrophages via CD44, releasing licofelone to reprogram Golgi-associated lipid metabolism, driving pro-inflammatory M1 macrophages toward an anti-inflammatory M2 phenotype. The study demonstrated that reprogramming sphingolipid and arachidonic acid metabolism can promote macrophage transition, highlighting metabolic remodeling as another viable strategy for restoring synovial homeostasis in OA²⁶³ (Figure 10B). Meanwhile, OA synovial macrophages undergo gasdermin D-dependent pyroptosis, inhibiting mitophagy, triggering mtDNA release, and activating the inflammatory pathway.²⁶⁷ Moving beyond polymeric platforms, nanogel-based strategy KZIF@HA has recently been engineered to finely tune macrophage phenotypes through microenvironment-responsive ion flux and metabolic remodeling, providing a next-generation strategy for achieving precise and durable immune homeostasis in OA therapy.²⁶⁸ Qi et al engineered MMP9-targeted RAPA@MPB-MMP9 NPs, integrating ROS-scavenging MPB NPs, mTORC1 inhibitor rapamycin and macrophage-targeting peptides. These NPs suppressed synovial macrophage pyroptosis, promoted mitophagy, inhibited cGAS–STING pathway, alleviated FLS senescence, and protected cartilage in CIOA mice with good biosafety.²⁶⁷

Additionally, recent research has proved the crucial contribution of NK cells in OA progression, including identify and eliminate senescent chondrocytes and synovial cells within the joint.^269,270 Zhang et al developed photoactivatable exosenolytics which recruit NK cells upon light activation, enhance their grip on senescent cells, and activate the cGAS-STING pathway, effectively clearing senescent cells in OA mice, suppressing inflammation, and remodeling the immune microenvironment²⁶⁴ (Figure 10C and D). Besides, T cells participate in the adaptive immune response to OA, driving inflammation and cartilage destruction through pro-inflammatory subsets. Treg function leads to immune imbalance, collectively propelling disease progression.²⁷¹ A new strategy includes immunomodulatory nanoparticles loaded with collagen II and rapamycin. In OA mice, these nanoparticle induced antigen-specific anti-inflammatory Treg cells, shifted cytokine balance towards anti-inflammation, and reduced joint inflammation, ultimately protecting cartilage and alleviating pain. The approach presents a promising targeted strategy²⁶⁵ (Figure 10E).

By forming biomimetic cell membrane, participating metabolic progression, and ablating hyperactive M1 cells, or replacing them with self-regulated M2 surrogates, nanotherapeutic strategies convert immune cells function from cartilage destruction to joint protection. The convergence of multiple systems provides a multifunctional immunomodulatory approach capable of long-term suppression of synovial inflammation without immune compromise.

Nanotherapeutic Strategies Neutralizing Pro-Inflammatory Cytokines

Pro-inflammatory cytokines, particularly IL-1β, TNF, and IL-6, are key drivers of OA pathology.²⁷² Produced by chondrocytes, synovial macrophages, and osteoblasts, these cytokines orchestrate a destructive cascade: upregulating MMPs and prostaglandins, suppressing collagen synthesis, and driving cartilage degradation alongside subchondral bone resorption.⁹¹ Conventional systemic biologics targeting these cytokines face significant limitations, including immunosuppression, infection risk, and poor joint penetration.⁹⁴ Nanotherapeutic strategies including nanogels,^92,273 exosomes²⁷⁴ and functionalized nanoparticles²⁷⁵ now function as intra-articular cytokine traps, sequestering pro-inflammatory mediators, blocking inflammatory cascades, and protecting cartilage ECM while enhancing local drug efficacy through targeted delivery.⁹⁴

Recent advances have focused on composite nanosystems that integrate multiple functionalities into a single platform, simultaneously reducing cytokine burden, modulating immune cell activity, and enabling controlled drug release.²⁷⁶ Building upon the success of ozone therapy in OA,²⁷⁷ Wu et al⁹² fabricated an injectable thermo-responsive hydrogel loaded with an ozone-rich nanocomposite and D-mannose (O₃NPs@MHPCH). This system decreases IL-1β, IL-6, TNF-α, and iNOS levels while alleviating synovial inflammation, cartilage destruction, and subchondral bone remodeling. Meanwhile, Yang et al²⁴⁰ developed CPHs, a peptide dendrimer nanogel loaded with CORM-401 and coated with FA-HA, targeting activated macrophages to deplete ROS and trigger CO release, effectively suppressing pro-inflammatory cytokines and cartilage degradation through integrated oxidative stress and inflammatory modulation.

Immunoregulatory MSC-derived exosomes have emerged as potent cytokine modulators with intrinsic anti-inflammatory properties.²⁷⁸ Deer antler adipose-derived stem cell exosomes (ASC-Exos) enriched in miR-140 effectively suppress IL-6 and TNF-α secretion from OA chondrocytes while simultaneously inhibiting MMP13-mediated collagen degradation through the miR-140/MMP13 axis.²⁷⁹ Similarly, embryonic MSC-derived exosomes preserve chondrocyte phenotype by promoting collagen II synthesis and suppressing ADAMTS5 expression, creating a dual mechanism that both neutralizes inflammatory signals and prevents matrix breakdown.²⁷⁸ However, clinical translation of exosome-based therapies remains challenged by uncontrolled cargo release, uneven in situ distribution, and limited persistence.^280–282 To address these limitations, innovative strategies integrate immunoregulatory exosomes with 3D bioprinted hydrogel scaffolds (3D-BPH-Exos), enhancing stability and enabling targeted delivery to chondrocytes and cartilage tissue.²⁷⁴ This approach reduces IL-1β, TNF-α, and IFN-γ release while preventing chondrocyte apoptosis, offering improved therapeutic outcomes through sustained, localized cytokine neutralization.²⁷⁴

Collectively, these nano-platforms break the inflammatory cycle in OA by neutralizing pro-inflammatory cytokines from exosome-based modulation to smart hydrogel-enabled sustained release. Future designs should combine biologics with multi-responsive hydrogels for personalized, long-acting therapy capable of adapting to the evolving inflammatory microenvironment. Table 3 summarizes representative nanotherapeutic strategies targeting inflammation pathogenesis in OA.

Table 3 Representative Nanotherapeutic Strategies Targeting Inflammation Pathogenesis in OA

Conclusion and Perspectives

OA represents a paradigm shift from passive “wear-and-tear” degeneration to an active, multifactorial joint failure syndrome orchestrated by the pathological triad of cellular senescence, metabolic dysregulation, and chronic inflammation.^130,283 Conventional therapies remain largely palliative, offering symptomatic relief and often accompanied by significant adverse effects,^284,285 necessitating disease-modifying interventions that target these interconnected mechanisms.^286–288 Nanotherapeutic strategies have emerged as a transformative model, leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release to achieve spatiotemporally controlled drug delivery within the joint microenvironment.^{286,289–291} Besides, nanomaterials can be engineered to actively modulate key cellular processes, including inflammation, autophagy, and apoptosis, thereby supporting chondrocyte survival and matrix preservation. Expanding material interfaces with multiple immune cell populations may further refine local immune regulation. As delineated in this review, nano-enabled platforms demonstrate multimodal efficacy: senolytic delivery coupled with mitochondrial repair and autophagy activation rejuvenates the aging chondrocyte population;^8,292 ROS-scavenging nanozymes and metabolic modulators restore redox homeostasis and bioenergetic balance;²⁹³ immunoregulatory nanoparticles reprogram synovial macrophages from pro-inflammatory M1 to reparative M2 phenotypes, thereby disrupting the inflammatory feed-forward loop.^221,223 The convergence of these models positions nanomedicine not merely as a delivery vehicle, but as an active modulator of joint pathobiology. A systematic comparison of representative nanotherapeutic strategies for OA drug delivery is presented in Table 4, focusing on their delivery mechanisms, effects, and practical feasibility, and providing a clear overview of current strategies and design features.

Table 4 Systematic Comparison of Nanotherapeutic Strategies for OA Drug Delivery

Recent integration of nanotherapeutics with 3D and 4D printing represents a significant frontier in structural repair.^294,295 3D-printed scaffolds with customizable architecture and tunable mechanical properties offer superior recapitulation of native extracellular matrix, while nanocarrier incorporation enables spatially controlled drug release.^296–298 4D printing further introduces dynamic responsiveness to environmental triggers, creating microenvironment-adaptive interventions.²⁹⁹ Despite these advances, clinical translation requires coordinated progress across several areas. First, enhancing targeting precision and biosafety remains essential. Rational surface engineering and physicochemical optimization should achieve high cartilage specificity while minimizing off-target distribution and long-term toxicity. Second, predictive preclinical models are urgently needed. Joint organoid systems and advanced animal models that better recapitulate human OA pathology would provide more accurate evaluation of nanoparticle efficacy, biodistribution, and safety. Third, metabolic and immunological insights should inform nanoformulation design. Multi-targeted nanotherapies addressing metabolic reprogramming in chondrocytes and immunoregulatory modulation of the intra-articular milieu will likely yield superior outcomes. Fourth, addressing declining chondrocyte density in aged cartilage is fundamental. Future nanomaterials should integrate chondroprotective cues with pro-regenerative signals to stimulate endogenous cell proliferation and enhance transplanted cell survival. Finally, personalized nanomedicine approaches tailored to patient-specific disease phenotypes represent the future of OA management. Stratified therapeutic strategies based on biomarker profiles and disease subtypes will optimize clinical outcomes.

In conclusion, while the path to clinical application is fraught with challenges, the prospects of nanotechnology in OA treatment are encouraging. With continued research and innovation, nanomedical strategies have the potential to revolutionize the management of OA, offering patients more effective and safer treatment options.