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<journal-id journal-id-type="publisher-id">Front. Bioeng. Biotechnol.</journal-id>
<journal-title>Frontiers in Bioengineering and Biotechnology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Bioeng. Biotechnol.</abbrev-journal-title>
<issn pub-type="epub">2296-4185</issn>
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<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-id pub-id-type="publisher-id">1664799</article-id>
<article-id pub-id-type="doi">10.3389/fbioe.2025.1664799</article-id>
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<subject>Bioengineering and Biotechnology</subject>
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<subject>Review</subject>
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<title-group>
<article-title>Nanomaterials in the diagnosis and therapy of osteoarthritis: current research advances and future clinical prospects</article-title>
<alt-title alt-title-type="left-running-head">Li et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fbioe.2025.1664799">10.3389/fbioe.2025.1664799</ext-link>
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<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Li</surname>
<given-names>Xin</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
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<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Shen</surname>
<given-names>Zeyan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Zhang</surname>
<given-names>Songou</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
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<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Yuke</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Lu</surname>
<given-names>Xuanyuan</given-names>
</name>
<xref ref-type="aff" rid="aff4">
<sup>4</sup>
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<xref ref-type="corresp" rid="c001">&#x2a;</xref>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Hu</surname>
<given-names>Xujun</given-names>
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<xref ref-type="aff" rid="aff4">
<sup>4</sup>
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<xref ref-type="corresp" rid="c001">&#x2a;</xref>
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<aff id="aff1">
<sup>1</sup>
<institution>School of Medicine, Shaoxing University</institution>, <addr-line>Shaoxing</addr-line>, <addr-line>Zhejiang</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Radiology, Shaoxing People&#x2019;s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Key Laboratory of Functional Molecular Imaging of Tumor and Interventional Diagnosis and Treatment of Shaoxing City</institution>, <addr-line>Shaoxing</addr-line>, <addr-line>Zhejiang</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>School of medicine, Ningbo university</institution>, <addr-line>Ningbo</addr-line>, <addr-line>Zhejiang</addr-line>, <country>China</country>
</aff>
<aff id="aff4">
<sup>4</sup>
<institution>Department of Orthopedic, Shaoxing People&#x2019;s Hospital, First Affiliated Hospital of Shaoxing University</institution>, <addr-line>Shaoxing</addr-line>, <addr-line>Zhejiang</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1692451/overview">Cheng Hu</ext-link>, Sichuan University, China</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2053673/overview">Yifan Li</ext-link>, Zhejiang University, China</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/3143297/overview">Heng Gong</ext-link>, Sichuan University, China</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Xujun Hu, <email>huxujun2022@163.com</email>; Xuanyuan Lu, <email>luxuanyuan@fjmu.edu.cn</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors share first authorship</p>
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<pub-date pub-type="epub">
<day>30</day>
<month>09</month>
<year>2025</year>
</pub-date>
<pub-date pub-type="collection">
<year>2025</year>
</pub-date>
<volume>13</volume>
<elocation-id>1664799</elocation-id>
<history>
<date date-type="received">
<day>15</day>
<month>07</month>
<year>2025</year>
</date>
<date date-type="accepted">
<day>22</day>
<month>09</month>
<year>2025</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2025 Li, Shen, Zhang, Chen, Lu and Hu.</copyright-statement>
<copyright-year>2025</copyright-year>
<copyright-holder>Li, Shen, Zhang, Chen, Lu and Hu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Osteoarthritis (OA), the most prevalent degenerative joint disorder, is characterized by progressive cartilage degradation, synovial inflammation, and functional impairment. Current treatments mainly alleviate symptoms without halting disease progression, and systemic drug administration often leads to poor absorption, short half-life, off-target effects, and adverse reactions. Recent advances in nanotechnology provide innovative solutions through nanomaterials with superior physicochemical properties, enabling targeted delivery, sustained release, and reduced toxicity. Compared with conventional therapies, nanotherapeutic strategies enhance treatment efficacy, support cartilage regeneration, and offer diagnostic potential. This review summarizes recent progress in nanomaterials for OA therapy, including liposomes, polymeric and inorganic nanoparticles, exosomes, gene delivery systems, and multifunctional platforms. We highlight their mechanisms, advantages, limitations, and translational potential, aiming to provide a comprehensive reference for future nanomedicine development in OA treatment.</p>
</abstract>
<kwd-group>
<kwd>nanoparticles</kwd>
<kwd>cartilage-targeting therapy</kwd>
<kwd>osteoarthritis</kwd>
<kwd>drug delivery</kwd>
<kwd>nanotherapeutic strategies</kwd>
</kwd-group>
<counts>
<page-count count="11"/>
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<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Biomaterials</meta-value>
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</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Osteoarthritis (OA) is a widespread joint condition marked by degeneration, impacting over 300 million individuals globally. It involves the progressive breakdown of joint cartilage, alongside changes in the underlying bone and inflammation of the synovial membrane. The likelihood of developing OA rises sharply as people age (<xref ref-type="bibr" rid="B3">Assi et al., 2023</xref>). Worldwide, among those aged 60 and older, more than 10% of men and 18% of women experience symptomatic OA (<xref ref-type="bibr" rid="B19">Cross et al., 2014</xref>). A primary contributor to disability among the elderly population, OA imposes an annual economic burden of approximately $100 billion in the US alone (<xref ref-type="bibr" rid="B11">Centers for Disease Control and Prevention CDC, 2013</xref>). The public health impact of OA has been intensified by the expanding elderly population, escalating obesity levels, and a surge in joint injuries (<xref ref-type="bibr" rid="B82">Takeuchi et al., 2021</xref>).</p>
<p>The pathophysiology of OA is multifactorial, involving inflammatory mediators such as cytokines (e.g., IL-1&#x3b2;, TNF-&#x3b1;), reactive oxygen/nitrogen species, and matrix metalloproteinases (MMPs), which contribute to cartilage matrix degradation, chronic synovial inflammation, and subchondral bone remodeling. (<xref ref-type="bibr" rid="B55">Loeser et al., 2012</xref>; <xref ref-type="bibr" rid="B62">Martel-Pelletier et al., 2016</xref>; <xref ref-type="bibr" rid="B44">Kumar et al., 2023</xref>). The cumulative effects of these processes manifest as pain, joint stiffness, and functional impairment, ultimately leading to disability (<xref ref-type="bibr" rid="B24">Goldring, 2012</xref>; <xref ref-type="bibr" rid="B8">Bruno et al., 2022</xref>). These pathological mechanisms directly inform the rational design of nanomaterials. For example, nanoparticles loaded with IL-1 receptor antagonists or TNF-&#x3b1; inhibitors target excessive cytokine signaling; ROS-responsive nanoplatforms mitigate oxidative stress in inflamed joints; MMP-sensitive delivery systems enable controlled drug release in cartilage degradation environments; and cartilage-targeting scaffolds address extracellular matrix loss. Recent findings from a synovium&#x2013;meniscus crosstalk study demonstrated that inflammatory interactions between these tissues may be a key driver of OA progression, providing direct evidence for pathogenic mechanisms within the OA microenvironment (<xref ref-type="bibr" rid="B96">Yu et al., 2024</xref>). Furthermore, <xref ref-type="bibr" rid="B48">Li K. et al. (2024)</xref> established an <italic>ex vivo</italic> osteochondral&#x2013;synovial coculture model that enables precise evaluation of candidate nanotherapies in a pathologically relevant OA microenvironment, offering a valuable platform for preclinical screening and dose&#x2013;safety optimization (<xref ref-type="bibr" rid="B48">Li K. et al., 2024</xref>). By aligning the unique physicochemical properties of nanomaterials with these pathological features, therapeutic interventions can be tailored for improved efficacy in OA management.</p>
<p>Current clinical management strategies&#x2014;including physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and intra-articular injections&#x2014;primarily alleviate symptoms without halting disease progression. Chronic systemic drug administration may induce severe adverse effects such as gastrointestinal complications, elevated cardiovascular risks, and osteoporosis (<xref ref-type="bibr" rid="B20">da Costa et al., 2017</xref>; <xref ref-type="bibr" rid="B81">Sinatti et al., 2022</xref>). Consequently, the development of therapeutic strategies aimed at long-term disease management and functional recovery is of paramount importance. Key pathogenic Mechanisms of OA, including chronic inflammation and cartilage degeneration, represent critical targets for novel interventions (<xref ref-type="bibr" rid="B66">Molnar et al., 2021</xref>).</p>
<p>Recent advances in nanotechnology demonstrate its potential for modulating inflammation and promoting cartilage regeneration, positioning targeted nanotherapy as a promising OA treatment strategy (<xref ref-type="bibr" rid="B16">Chen et al., 2025</xref>). Nanotechnology, an interdisciplinary field, investigates nanoparticles (NPs, typically 1&#x2013;100&#xa0;nm) that exhibit unique physicochemical properties, enabling diverse functionalities (<xref ref-type="bibr" rid="B68">Mulvaney, 2015</xref>; <xref ref-type="bibr" rid="B36">Jeevanandam et al., 2018</xref>; <xref ref-type="bibr" rid="B42">Joudeh and Linke, 2022</xref>) Numerous NP-based drug delivery systems&#x2014;including micelles, liposomes, dendrimers, organic NPs (polymeric/carbohydrate-based), carbon-based NPs, and inorganic NPs&#x2014;have been explored for intravenous or intra-articular OA therapy (<xref ref-type="bibr" rid="B42">Joudeh and Linke, 2022</xref>). These nanotherapeutic approaches enhance drug targeting, delivery efficiency, solubility, and stability while reducing adverse effects (<xref ref-type="bibr" rid="B29">Gu et al., 2013</xref>; <xref ref-type="bibr" rid="B2">An et al., 2023</xref>). With their exceptional properties (high surface-area ratio, tunable mechanical properties, biocompatibility), nanomaterials have spurred advancements in developing NP-based therapies to alleviate symptoms and modify OA progression.</p>
<p>This review systematically summarizes recent advances in nanomaterials for OA diagnosis and treatment, including design strategies of functional NPs, their mechanisms of action, and clinical translation potential. Future directions and challenges for multifunctional NPs are also discussed.</p>
<p>Literature Search Strategy: Relevant studies were identified through searches of PubMed, Web of Science, and Scopus databases between January 2019 and March 2025 using combinations of keywords: &#x201c;osteoarthritis,&#x201d; &#x201c;nanoparticles,&#x201d; &#x201c;drug delivery,&#x201d; &#x201c;hydrogel,&#x201d; &#x201c;scaffold,&#x201d; &#x201c;imaging,&#x201d; and &#x201c;exosomes.&#x201d; Both original research and high-quality reviews were considered. Articles were screened based on relevance, citation impact, and innovation. Studies focusing on non-nanomaterial approaches were excluded.</p>
</sec>
<sec id="s2">
<title>2 Applications of nanomaterials in drug delivery</title>
<p>What the research suggest is that nanoparticles, due to what be their exceptional capabilities in precise drug delivery and controlled release, tend to serve as valuable instruments for seemingly improving the effectiveness of various medications or potentially supporting the identification of OA (<xref ref-type="bibr" rid="B60">Maghsoudlou et al., 2020</xref>). The physical and chemical characteristics of nanoparticles differ based on their dimensions and shapes, which can ostensibly be adjusted during production, thus seemingly enabling what tends to be the creation of more tailored and largely individualized therapeutic approaches for diverse medical conditions (<xref ref-type="bibr" rid="B34">Hoshyar et al., 2016</xref>). For example, within this broader analytical framework, nanoparticles ranging from approximately 50&#x2013;100&#xa0;nm in size demonstrate a tendency to concentrate in the inflamed joints of mice, making them apparently highly suitable for what be the accurate transport of bioactive compounds in OA therapy (<xref ref-type="bibr" rid="B89">Wei et al., 2021</xref>). What appears particularly significant about these findings is that rod-shaped viral nanoparticles generally indicate greater tissue penetration than spherical nanoparticles, what this tends to suggest, therefore, is their suitability for deep delivery into articular cartilage in OA therapy (<xref ref-type="bibr" rid="B63">Maturavongsadit et al., 2016</xref>). Additionally, given the complexity of these theoretical relationships, different nanomaterials exhibit what seems to constitute variations in biocompatibility, stability, and release kinetics (<xref ref-type="bibr" rid="B83">Tang et al., 2022</xref>).</p>
<p>Achieving optimal therapeutic outcomes in OA largely depend on the localized administration of bioactive compounds to affected areas. What emerge from current research is that nanocarrier systems tend to offer what be a versatile platform for this purpose, as their exterior can be engineered to impart specialized biological functionalities, including what represent augmented biocompatibility, site-specific transport, and optimized intracellular absorption (<xref ref-type="bibr" rid="B69">Nethi et al., 2019</xref>). Within this broader analytical framework, the spatial accuracy of therapeutic agent distribution to pathological regions constitute a fundamental requirement for successful OA intervention. What the evidence reveal is that nanomaterials can be engineered through various mechanisms (e.g., passive targeting, active targeting, and stimulus-responsive targeting) to target specific cells, tissues, or organs (<xref ref-type="bibr" rid="B88">Wang et al., 2021b</xref>). Passive targeting rely on the natural accumulation of NPs within inflamed OA joints, apparently driven by the enhanced permeability and retention (EPR) phenomenon. What appears particularly significant about these findings is that this mechanism leverage the compromised vascular integrity in inflamed tissues, allowing nanoparticles to predominantly concentrate in these regions and subsequently improve their internalization by targeted cells (<xref ref-type="bibr" rid="B5">Bertrand et al., 2014</xref>). Given the complexity of these theoretical relationships, active targeting involve conjugating ligands or peptides to the nanoparticle surface, which recognize and bind to specific receptors on target cells (<xref ref-type="bibr" rid="B87">Wang et al., 2021a</xref>).</p>
<p>In light of these methodological considerations, what the analysis tends to support is that NPs offer a viable solution to overcome limitations typically associated with traditional treatment methods, seemingly addressing what be critical issues such as drug transport efficiency, biological availability, and site-specific therapeutic interventions (<xref ref-type="bibr" rid="B30">Guo et al., 2022</xref>). What seems especially noteworthy in this analytical context is that their unique physicochemical properties and multifunctionality have opened new avenues for what tends to suggest enhanced treatment efficacy and facilitated personalized patient care. What emerge from this evidence is that with continued advancements in nanotechnology, the clinical translation of these innovations hold substantial potential for what constitute a transformation of traditional medical paradigms and what represent improved long-term personalized management strategies for the majority of OA patients.</p>
</sec>
<sec id="s3">
<title>3 Classification of nanoparticle-based drug delivery systems for OA treatment</title>
<sec id="s3-1">
<title>3.1 Liposomes</title>
<p>Biologically active compounds, including growth-promoting factors, cell signaling molecules, and inflammation-suppressing agents, are essential for facilitating tissue repair and reducing inflammatory responses in osteoarthritis. However, the clinical application of many pharmacologically active small-molecule drugs is significantly limited by their short biological half-lives and systemic administration-induced off-target effects, which reduce therapeutic efficacy (<xref ref-type="bibr" rid="B72">Patra et al., 2018</xref>). Nanoparticles can facilitate localized drug delivery to the injury site, prolong drug release, enhance therapeutic outcomes, and minimize adverse effects (<xref ref-type="bibr" rid="B72">Patra et al., 2018</xref>).</p>
<p>Liposomes (Lipo) are spherical nanoparticles composed of a lipid bilayer, capable of encapsulating both hydrophilic and hydrophobic drug molecules (<xref ref-type="bibr" rid="B6">Bozzuto and Molinari, 2015</xref>). By engineering surface properties, liposome-based nanoparticles can enhance the efficacy and delivery performance of diverse pharmaceutical agents. For instance, A recent study by Chang et al. introduced an innovative osteoarthritis treatment platform utilizing hyaluronan-functionalized liposomes (HA-Lipo) encapsulating diclofenac and dexamethasone (DIC/DEX), designated as HA-Lipo-DIC/DEX, for joint pain management and extended therapeutic effects (<xref ref-type="bibr" rid="B12">Chang et al., 2021</xref>). Experimental results revealed that this nanocarrier system reached optimal therapeutic concentrations within 4&#xa0;h post-administration while maintaining controlled drug release for over 168&#xa0;h with minimal cytotoxic effects (<xref ref-type="bibr" rid="B12">Chang et al., 2021</xref>). Administration via intra-articular injection demonstrated substantial anti-inflammatory activity in knee joints, achieving a 77.5% &#xb1; 5.1% reduction in inflammatory markers from initial levels following a single treatment over a 4-week observation period (<xref ref-type="bibr" rid="B12">Chang et al., 2021</xref>). These outcomes indicate the potential of this nanotherapeutic approach as an effective strategy for managing osteoarthritis-related pain and inflammation (<xref ref-type="bibr" rid="B12">Chang et al., 2021</xref>).</p>
<p>Liposomes can be actively or passively targeted to their delivery sites by leveraging ligand-receptor interactions between surface-modified ligands and receptors present at the target site, thereby reducing systemic side effects (<xref ref-type="bibr" rid="B99">Zhang et al., 2021</xref>; <xref ref-type="bibr" rid="B54">Liu et al., 2022</xref>; <xref ref-type="bibr" rid="B98">Zha et al., 2024</xref>). Adenosine, a key autocrine cytokine for maintaining cartilage homeostasis, has been incorporated into biodegradable nanoparticles to prolong its therapeutic effects. Liu et al. reported the synthesis of adenosine receptor agonist-loaded poly (ethylene glycol)-b-poly (lactic acid) (PEG-b-PLA) nanoparticles for OA treatment, demonstrating enhanced therapeutic duration (<xref ref-type="bibr" rid="B51">Liu et al., 2019</xref>). The A2A receptor, a subtype of adenosine receptors, was targeted by Corciulo et al., who encapsulated adenosine and an A2A receptor agonist in liposomes to delay OA progression in obesity-induced post-traumatic OA models in mice and rats (<xref ref-type="bibr" rid="B18">Corciulo et al., 2020</xref>). Zhong et al. developed an actively loaded liposomal composite reinforced with chitosan to enhance water solubility and divalent metal ions (Ca<sup>2&#x2b;</sup>) to improve encapsulation efficiency (<xref ref-type="bibr" rid="B104">Zhong et al., 2023</xref>). <italic>Ex vivo</italic> and <italic>in vivo</italic> evaluations revealed that this nanoparticle significantly ameliorated chondrocyte apoptosis and extracellular matrix degeneration by restoring the inflammatory microenvironment in OA joints (<xref ref-type="bibr" rid="B104">Zhong et al., 2023</xref>). While these studies highlight the advantages of nanoparticles in targeted OA drug delivery, challenges remain, such as competitive binding between nanomaterials and target receptors due to multiple ligands and receptors <italic>in vivo</italic> (<xref ref-type="bibr" rid="B17">Cheng et al., 2023</xref>).</p>
<p>For IA management of OA pain and synovitis, hyaluronan-functionalized or receptor-targeted liposomes enable co-delivery of NSAIDs/corticosteroids with extended local exposure. Key risks include burst release and competition with endogenous ligands; design should prioritize release-rate control, ligand density optimization, and reproducible CMC parameters to de-risk translation.</p>
</sec>
<sec id="s3-2">
<title>3.2 Polymeric nanoparticles</title>
<p>Polymeric nanoparticles have garnered substantial attention in nanomedicine, largely due to what be their adaptable structural properties, relatively straightforward fabrication processes, and what be enhanced stability compared to alternative nanoparticle systems (<xref ref-type="bibr" rid="B74">Pontes et al., 2022</xref>). What the evidence tends to suggest, for instance, is that poly (lactic-co-glycolic acid) (PLGA) NPs containing p66shc-siRNA seem to reduce p66shc expression and apparently mitigate pain, cartilage degradation, and inflammatory cytokine release caused by monosodium iodoacetate (MIA) in rat knee joints (<xref ref-type="bibr" rid="B78">Shin et al., 2020</xref>). The epidermal growth factor receptor (EGFR), a cell surface receptor, maintain superficial chondrocyte populations, cartilage lubrication, collagen organization, and what might be characterized as cartilage mechanical strength (<xref ref-type="bibr" rid="B37">Jia et al., 2016</xref>). What seems particularly noteworthy in this analytical context is the cartilage-targeting strategy utilizing polymeric nanoparticles that was introduced by <xref ref-type="bibr" rid="B89">Wei et al. (2021)</xref>. Their research suggest that micellar nanoparticles, when combined with a strong EGFR ligand, tend to display what be remarkable stability, minimal toxicity, apparently extended joint retention, and what represent superior cartilage absorption and penetration properties (<xref ref-type="bibr" rid="B89">Wei et al., 2021</xref>). What the data suggest is that, through intra-articular administration, these engineered nanoparticles significantly alleviate cartilage degradation, subchondral bone hardening, and pain in a mouse model of osteoarthritis (<xref ref-type="bibr" rid="B89">Wei et al., 2021</xref>). Within these evolving conceptual parameters, Maudens et al. investigated a highly kartogenin-loaded nanocrystalline polymeric particle (NPP) system, which generally indicate enhanced chondrogenic and chondroprotective effects (<xref ref-type="bibr" rid="B64">Maudens et al., 2018</xref>). Given the complexity of these theoretical relationships, a triamcinolone acetonide extended-release (ER) formulation, authorized in the U.S. for osteoarthritis pain relief, facilitate the gradual release of the corticosteroid from PLGA microspheres into what seems to constitute synovial tissue (<xref ref-type="bibr" rid="B70">Paik et al., 2019</xref>). What this approach tends to indicate is an extended therapeutic effect while presumably minimizing systemic adverse reactions (<xref ref-type="bibr" rid="B70">Paik et al., 2019</xref>). What emerge from this evidence, collectively, is that these findings seem to point toward the practicality and relative safety of utilizing polymeric nanoparticles in the treatment of osteoarthritis.</p>
<p>PLGA-based carriers are attractive due to established manufacturability and tunable kinetics; however, acidic microclimates during polymer erosion and heterogeneous joint distribution warrant attention. Future studies should report effect sizes with variance, intra-articular residence times, and head-to-head comparisons to standard IA steroids or HA.</p>
<p>Compared with polymeric and inorganic nanoparticles, liposomes offer superior biocompatibility and drug encapsulation efficiency, but they may suffer from rapid clearance and limited long-term stability. In contrast, polymeric nanoparticles often provide longer-term release profiles and higher mechanical stability but may involve more complex manufacturing processes. This comparison underscores the need to select nanoparticles based not only on efficacy but also on translational feasibility and safety.</p>
</sec>
<sec id="s3-3">
<title>3.3 Inorganic nanoparticles</title>
<p>Typical inorganic nanoparticles&#x2014;including metals (e.g., silver, iron, gold) and metal oxides&#x2014;have been widely leveraged across biomedical applications due to their tunable size/shape, high surface area, magnetic/optical responsiveness, and ease of surface functionalization for biocompatibility and targeting (<xref ref-type="bibr" rid="B85">Valot et al., 2021</xref>; <xref ref-type="bibr" rid="B75">Sang et al., 2023</xref>). In OA, these features translate into opportunities for joint lubrication enhancement, imaging contrast, photothermal or magnetically assisted therapy, and controlled intra-articular drug delivery (<xref ref-type="bibr" rid="B85">Valot et al., 2021</xref>; <xref ref-type="bibr" rid="B75">Sang et al., 2023</xref>). Alloyed or doped systems (two or more metals) often provide greater structural stability, reduced ion dissolution, and fine-tuned catalytic/photophysical properties compared with single-metal counterparts, which can improve performance under physiological conditions. (<xref ref-type="bibr" rid="B35">Huynh et al., 2020</xref>). Given the complexity of these theoretical relationships, Gong et al. developed what constitute a fluorinated graphene (FG) nanosystem with dual functionality&#x2014;what seems to be long-term lubrication and thermo-responsive drug release&#x2014;leveraging what the evidence reveal as the ostensibly outstanding near-infrared (NIR) absorption capabilities and what be highly efficient photothermal conversion properties of FG to apparently achieve NIR-triggered drug release (<xref ref-type="bibr" rid="B25">Gong et al., 2023</xref>). As proof-of-concept for therapeutic activity, silver nanoparticles have shown anti-osteoarthritic efficacy in murine models&#x2014;attenuating inflammatory mediators and cartilage degeneration&#x2014;supporting the potential of inorganic nanomaterials as active agents rather than inert carriers alone (<xref ref-type="bibr" rid="B75">Sang et al., 2023</xref>). In parallel, magnetic nanoparticle platforms (e.g., superparamagnetic iron oxide) enable spatially guided, intracartilaginous delivery of chondroprotective molecules and growth-factor mimetics under external magnetic fields, improving retention and penetration within dense cartilage matrices and yielding superior histologic and micro-CT outcomes versus free drug (<xref ref-type="bibr" rid="B38">Jiang et al., 2022</xref>). Such magnetically assisted strategies directly address two major hurdles in OA therapy&#x2014;rapid joint clearance and poor matrix penetration&#x2014;while maintaining intra-articular localization to limit systemic exposure (<xref ref-type="bibr" rid="B38">Jiang et al., 2022</xref>).</p>
<p>Collectively, these advances underscore the promise of engineered inorganic and alloy/doped nanoparticles for OA management. Key next steps include optimizing long-term biocompatibility/biodegradability, minimizing metal-ion&#x2013;related cytotoxicity, validating safe and efficient on-demand activation (e.g., magnetic or photothermal triggers) <italic>in vivo</italic>, and establishing robust manufacturing/quality frameworks to support clinical translation.</p>
</sec>
<sec id="s3-4">
<title>3.4 Exosomes</title>
<p>Exosomes are membrane-bound vesicles measuring approximately 30&#x2013;150&#xa0;nm in diameter, which encapsulate complex molecular processes occurring in their parent cells (<xref ref-type="bibr" rid="B52">Liu et al., 2020</xref>). Through what be the transport of proteins, lipids, mRNAs, miRNAs, lncRNAs, and DNA, exosomes tend to mediate what be critical biological functions including cellular homeostasis maintenance, debris clearance, intercellular and interorgan communication, and targeted molecular delivery (<xref ref-type="bibr" rid="B50">Liang et al., 2021</xref>; <xref ref-type="bibr" rid="B43">Krylova and Feng, 2023</xref>). He et al. demonstrated that bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) significantly upregulated COL2A1 protein expression while downregulating MMP13 in cartilage tissue within a rat OA model (<xref ref-type="bibr" rid="B31">He et al., 2020</xref>). These exosomes effectively promoted cartilage repair, enhanced extracellular matrix (ECM) synthesis, and alleviated knee joint pain in OA rats (<xref ref-type="bibr" rid="B31">He et al., 2020</xref>). Chen et al. developed an injectable microgel system (CAP/FGF18-hyEXO@HMs) encapsulating hybrid exosomes (CAP/FGF18-hyEXO). By combining <italic>in vivo</italic> FGF18 gene editing with sustained lubrication, this system synergistically enhanced cartilage regeneration, reduced inflammation, and prevented ECM degradation in both <italic>ex vivo</italic> and <italic>in vivo</italic> settings (<xref ref-type="bibr" rid="B15">Chen M. et al., 2024</xref>). What appears particularly significant about these findings, within this broader analytical framework, is that with advancing exosome research, their clinical translational potential for OA treatment have become increasingly evident, which suggest what tends to represent a pathway for what might be considered novel therapeutic strategies (<xref ref-type="table" rid="T1">Table 1</xref>).</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Comparative evaluation of nanomaterials for osteoarthritis therapy.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Nanomaterial type</th>
<th align="left">Merits</th>
<th align="left">Limitations</th>
<th align="left">Translational potential</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Liposomes</td>
<td align="left">High biocompatibility; versatile drug encapsulation (hydrophilic and hydrophobic); surface easily modifiable</td>
<td align="left">Rapid clearance; limited long-term stability; potential leakage of drugs</td>
<td align="left">Clinically advanced; several formulations tested in trials; suitable for intra-articular delivery</td>
</tr>
<tr>
<td align="left">Polymeric Nanoparticles</td>
<td align="left">Sustained and controlled release; mechanical stability; tunable degradation rates</td>
<td align="left">Complex manufacturing; possible immunogenicity; regulatory hurdles</td>
<td align="left">High potential for personalized therapy; some formulations approved for other diseases</td>
</tr>
<tr>
<td align="left">Inorganic Nanoparticles</td>
<td align="left">Multifunctional (diagnosis &#x2b; therapy); strong mechanical and chemical stability; imaging potential</td>
<td align="left">Concerns about long-term biosafety and toxicity; accumulation risk in tissues</td>
<td align="left">Promising for theranostics but limited clinical translation so far</td>
</tr>
<tr>
<td align="left">Exosomes</td>
<td align="left">Excellent biological compatibility; natural intercellular communication; intrinsic targeting ability</td>
<td align="left">Scalability and standardization challenges; complex isolation procedures</td>
<td align="left">Emerging as a next-generation therapeutic; high research interest but early-stage clinical use</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec id="s4">
<title>4 Multifunctional nanoparticle strategy</title>
<p>With the advancement of nanotechnology and further research, novel properties and functions of nanomaterials continue to be discovered, enabling scholars to develop diverse therapeutic strategies for OA based on these unique characteristics.</p>
<sec id="s4-1">
<title>4.1 Gene delivery nanoparticles</title>
<p>Gene therapy has emerged as a cutting-edge strategy for addressing osteoarthritis (OA), offering the possibility of modifying disease progression at the molecular level rather than merely alleviating symptoms. Nanoparticles (NPs) provide an effective platform for targeted delivery of therapeutic genes to damaged joint tissues, owing to their tunable physicochemical properties, biocompatibility, and ability to cross biological barriers. For example, Cai et al. designed an innovative nanoparticle system encapsulating plasmid DNA (pDNA) encoding transforming growth factor-&#x3b2;1 (TGF-&#x3b2;1), which was used to modify mesenchymal stem cells (MSCs) (<xref ref-type="bibr" rid="B9">Cai et al., 2023</xref>). This strategy enhanced MSC-mediated cartilage repair, as the modified cells exhibited improved proliferation and superior transfection efficiency, leading to significantly greater regeneration in both <italic>ex vivo</italic> and <italic>in vivo</italic> OA models (<xref ref-type="bibr" rid="B9">Cai et al., 2023</xref>). Beyond growth factor delivery, gene-loaded nanoparticles have been engineered to regulate critical molecular pathways implicated in OA pathogenesis, including chondrocyte apoptosis, extracellular matrix degradation, and inflammatory cascades. For instance, chitosan&#x2013;hyaluronic acid hybrid nanoparticles carrying SOX9 or RUNX2 gene constructs have demonstrated the ability to promote chondrogenic differentiation and inhibit hypertrophy of chondrocytes, thereby maintaining cartilage homeostasis (<xref ref-type="bibr" rid="B56">Lu et al., 2014</xref>).</p>
<p>Beyond growth factor delivery, recent strategies have targeted both inflammatory signaling and catabolic enzymes via advanced gene editing tools. A notable study by Ponta et al. developed a non-viral CRISPR-Cas9 RNP (ribonucleoprotein) delivery protocol for primary human chondrocytes and other cartilaginous tissues, achieving &#x223c;90% knockout efficiency of RELA (a key NF-&#x3ba;B subunit) and demonstrating reduced inflammatory responses and improved matrix retention under cytokine (e.g., IL-1&#x3b2;) challenge (<xref ref-type="bibr" rid="B73">Ponta et al., 2024</xref>). This underscores the potential of gene editing in attenuating the inflammatory cascade in OA.</p>
<p>However, several challenges remain: achieving sustained and spatiotemporally controlled expression of therapeutic genes in the joint environment; minimizing immune responses and off-target effects; improving penetration into dense cartilage matrix; and ensuring translational feasibility (manufacturing, safety, regulatory approval). Future work should aim to develop stimuli-responsive nanoparticles (e.g., responding to pH, oxidative stress, enzymatic activity), combined gene/gene-editing &#x2b; regenerative strategies (stem cells or scaffold integration), and clinically relevant delivery routes for intraarticular application.</p>
</sec>
<sec id="s4-2">
<title>4.2 Anti-inflammatory drug-loaded nanoparticles</title>
<p>OA is a chronic disorder involving complex metabolic and inflammatory processes, where inflammation plays a pivotal role in disease progression (<xref ref-type="bibr" rid="B33">Hills, 2000</xref>). NPs have been specifically designed for the precise delivery of anti-inflammatory compounds, particularly those targeting critical inflammatory mediators like IL-1&#x3b2; and TNF-&#x3b1; (<xref ref-type="bibr" rid="B14">Chen L. et al., 2024</xref>). Research has shown that nanoparticles loaded with IL-1 receptor antagonist (IL-1Ra) effectively reduce synovitis and slow cartilage degradation (<xref ref-type="bibr" rid="B90">Whitmire et al., 2012</xref>). In OA, the balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophage phenotypes within the joint is pivotal (<xref ref-type="bibr" rid="B21">Dai et al., 2018</xref>). M2 macrophages, for their anti-inflammatory properties, offer significant therapeutic promise for OA (<xref ref-type="bibr" rid="B21">Dai et al., 2018</xref>). Teo et al. engineered gold NPs coated with M2 macrophage membranes (Au-M2 NPs), which effectively reduced MMP13 expression triggered by IL-1&#x3b2; and significantly suppressed nitric oxide release induced by IL-1&#x3b2;, leading to decreased inflammation and reduced matrix degradation (<xref ref-type="bibr" rid="B84">Teo et al., 2022</xref>). Yu et al. designed IA-ZIF-8@HMs for OA treatment, which possess both pH-responsive and proton acid-responsive properties, with IA modulating joint inflammation and intracellular oxidative stress (<xref ref-type="bibr" rid="B95">Yu et al., 2023</xref>). Jin et al. fabricated an epigallocatechin gallate (EGCG)-loaded hyaluronic acid (HA)/gelatin composite hydrogel, experimentally validated for its effective anti-inflammatory and osteogenic capabilities in a surgically induced OA model (<xref ref-type="bibr" rid="B40">Jin et al., 2020</xref>). Additionally, researchers developed PL407-PL338-HA-SFN hydrogels as a drug delivery platform to release sulforaphane (SFN), which downregulates the NF-&#x3ba;B pathway to reduce metalloproteinase expression, thereby treating OA (<xref ref-type="bibr" rid="B67">Monteiro Do Nascimento et al., 2021</xref>).</p>
<p>In addition to anti-inflammatory medications, nanoparticles can be engineered to carry a range of therapeutic agents, enabling them to deliver multiple beneficial effects. For example, antibiotic-delivering NPs have been explored. Feng et al. developed PLGA NPs loaded with doxycycline (DOXY) and incorporated them into poly (L-lactic acid) (PLLA) scaffolds, achieving sustained local antibiotic release for prolonged antibacterial efficacy (<xref ref-type="bibr" rid="B23">Feng et al., 2010</xref>). Another study demonstrated that injectable polyethylene glycol (PEG) hydrogels delivering lysostaphin ensured efficient localized delivery, effectively treating <italic>Staphylococcus aureus</italic> infections in fractures (<xref ref-type="bibr" rid="B41">Johnson et al., 2018</xref>).</p>
</sec>
<sec id="s4-3">
<title>4.3 ROS-sensitive nanoparticles</title>
<p>Reactive oxygen species (ROS), highly unstable molecules mainly produced by NADPH oxidases and mitochondrial activity, are critically involved in the pathological mechanisms underlying osteoarthritis. Li et al. developed a ROS-responsive functional nanoplatform for OA therapy, comprising borate-stabilized polyphenol-poloxamer assemblies loaded with Dex (<xref ref-type="bibr" rid="B47">Li et al., 2021</xref>). This nanomedicine exhibited ROS-triggered drug release kinetics and ROS-scavenging efficacy, effectively suppressing ROS and nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages, demonstrating therapeutic potential for OA (<xref ref-type="bibr" rid="B47">Li et al., 2021</xref>). Lu et al. engineered dual pH- and ROS-responsive nanoparticles loaded with methylprednisolone (MPS) and modified with arginine-glycine-aspartate (RGD) (<xref ref-type="bibr" rid="B58">Lu Y. et al., 2023</xref>). These nanoparticles significantly inhibited interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-&#x3b1;) expression in the joints of collagen-induced arthritis (CIA) mice, efficiently attenuating joint degradation through the suppression of the NF-&#x3ba;B signaling pathway (<xref ref-type="bibr" rid="B58">Lu Y. et al., 2023</xref>). Lv et al. proposed d-RuO<sub>2</sub> nanospheres exhibiting exceptional nanozyme antioxidant activity. <italic>Ex vivo</italic> experiments confirmed that these nanospheres markedly reduced intracellular ROS levels and downregulated key inflammatory markers, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-&#x3b1;, and interleukin-1&#x3b2; (IL-1&#x3b2;) (<xref ref-type="bibr" rid="B59">Lv et al., 2025</xref>). <italic>In vivo</italic>, d-RuO<sub>2</sub> alleviated synovitis, cartilage degeneration, and bone remodeling by inhibiting the ROS/NLRP3/caspase-1 signaling pathway, thereby delaying OA progression (<xref ref-type="bibr" rid="B59">Lv et al., 2025</xref>). Yu et al. engineered KGN/Dex-TSPBA@WHMs, a system capable of targeting cartilage specifically, efficiently eliminating ROS, and releasing drugs in response to ROS levels. This innovation shows promising potential for facilitating the regeneration of injured cartilage (<xref ref-type="bibr" rid="B94">Yu et al., 2022</xref>). Chondrocyte ferroptosis has emerged as a critical therapeutic target in OA (<xref ref-type="bibr" rid="B10">Cao et al., 2023</xref>). Sheng et al. developed fenofibrate (FN)-loaded nanoparticles (FN-CNPs) with ROS-responsive properties. These nanoparticles effectively reduced osteoarthritis progression by regulating ROS levels, enhancing the antioxidant defense system, and improving lipid metabolism in chondrocytes, ultimately preventing ferroptosis in these cells (<xref ref-type="bibr" rid="B77">Sheng et al., 2025</xref>).</p>
</sec>
<sec id="s4-4">
<title>4.4 Stimuli-responsive nanoparticles</title>
<p>Stimuli-responsive nanoparticles release their encapsulated drugs only upon exposure to appropriate triggers or specific conditions. Disease-associated local microenvironmental factors, internal factors like temperature, pH, and oxidative stress, as well as external triggers such as NIR light, offer valuable design principles for creating functionally tailored nanoparticles (<xref ref-type="bibr" rid="B46">Lawson et al., 2021b</xref>). For instance, Chen et al. combined a photothermally triggered nitric oxide (NO) nanogenerator with small interfering RNA (siRNA), yielding NO-Hb@siRNA@PLGA-PEG (NHsPP) (<xref ref-type="bibr" rid="B13">Chen et al., 2019</xref>). This mechanism efficiently transforms absorbed NIR light into adequate thermal energy, which induces NO production and subsequently inhibits inflammation driven by macrophages (<xref ref-type="bibr" rid="B13">Chen et al., 2019</xref>).</p>
<p>Under physiological conditions, the pH of synovial fluid in the knee joint ranges between 7.35 and 7.45 (<xref ref-type="bibr" rid="B92">Xiong et al., 2020</xref>). However, in OA, the pH of the joint microenvironment can decrease to below 6.0 (<xref ref-type="bibr" rid="B80">Shirazian et al., 2024</xref>). Consequently, pH-sensitive nanoplatforms have been developed for targeted drug delivery in OA treatment. For example, researchers have fabricated pH-responsive PLGA NPs co-encapsulated with ammonium bicarbonate (NH4HCO3), which effectively delay OA progression (<xref ref-type="bibr" rid="B97">Zerrillo et al., 2019</xref>). Liu et al. designed a pH-sensitive nanomedicine (TP@NPs) by encapsulating triptolide (TP) into star-shaped amphiphilic block copolymers (POSS-PCL-b-PDMAEMA), demonstrating significant chondroprotective and anti-inflammatory effects (<xref ref-type="bibr" rid="B53">Liu et al., 2021</xref>). Jiang et al. developed an acidic environment-responsive hydrogel (NBIF@ZIF-8 MOFs) based on zeolitic imidazolate framework-8 (ZIF-8), enabling stimulus-triggered release of neobavaisoflavone (NBIF). This system synergistically modulates immune responses and promotes cartilage defect repair through the combined action of NBIF and the hydrogel matrix (<xref ref-type="bibr" rid="B39">Jiang et al., 2023</xref>).</p>
</sec>
<sec id="s4-5">
<title>4.5 Cartilage repair and regeneration scaffolds</title>
<p>Biomaterial scaffolds incorporating nanotechnology have become indispensable in cartilage tissue engineering, as they provide a three-dimensional (3D) extracellular matrix&#x2013;mimicking architecture that not only facilitates cell adhesion, proliferation, and differentiation but also enables precise spatial and temporal delivery of bioactive molecules. Such scaffolds can be engineered to release growth-promoting and anti-inflammatory agents in a controlled manner, thereby fostering cartilage repair while simultaneously supporting subchondral bone regeneration.</p>
<p>Consistent with the &#x2018;scaffold &#xd7; gene therapy&#x2019; strategy discussed above, Venkatesan et al., used an alginate hydrogel to guide rAAV-mediated delivery of FGF-2/TGF-&#x3b2;, significantly enhancing extracellular matrix synthesis by human meniscal fibrochondrocytes and promoting tissue repair (<xref ref-type="bibr" rid="B86">Venkatesan et al., 2024</xref>). In a related study, Zhang et al. explored the use of a pH-sensitive metal-organic framework (MOF), MIL-101-NH2, to simultaneously deliver the anti-inflammatory agent curcumin (CCM) and siRNA designed to inhibit hypoxia-inducible factor-2&#x3b1; (HIF-2) (<xref ref-type="bibr" rid="B101">Zhang Z.-J. et al., 2023</xref>). By silencing the HIF-2&#x3b1; gene and suppressing inflammatory responses and cartilage degeneration in OA, this MOF demonstrated promising therapeutic potential for OA treatment (<xref ref-type="bibr" rid="B101">Zhang Z.-J. et al., 2023</xref>). Shin et al. designed a novel mesenchymal stem cell (MSC) platform, named Edu-MSCs-AuS-TA, where gold nanoparticles (AuNPs) loaded with triamcinolone acetonide (TA) were attached to the MSC surface to amplify their anti-inflammatory properties (<xref ref-type="bibr" rid="B79">Shin et al., 2024</xref>). By combining AuNPs with MSCs and utilizing near-infrared laser-assisted photothermal therapy (PTT), this approach promoted anti-inflammatory effects and induced macrophage repolarization (<xref ref-type="bibr" rid="B79">Shin et al., 2024</xref>). Notably, it significantly alleviated arthritis-associated pain, improved overall motor function, and even induced cartilage regeneration in advanced-stage arthritis models (<xref ref-type="bibr" rid="B79">Shin et al., 2024</xref>). Recent advances further underscore the versatility of nanostructured scaffolds: hydrogel&#x2013;nanoparticle composites can provide mechanical reinforcement, lubricating function, and ROS/pH-responsiveness, thus allowing drug release tailored to the inflamed OA microenvironment (<xref ref-type="bibr" rid="B94">Yu et al., 2022</xref>). Moreover, exosome-functionalized nanoscaffolds have been shown to promote chondrocyte proliferation and inhibit apoptosis, offering a synergistic strategy that couples regenerative cell therapy with nanomaterial-based delivery platforms (<xref ref-type="bibr" rid="B15">Chen M. et al., 2024</xref>). In parallel, recent studies in chronic inflammatory wound models have demonstrated the broad versatility of nanostructured hydrogels. For example, Gong et al. engineered a metal&#x2013;polyphenol nanocomposite hydrogel capable of reprogramming the metabolic microenvironment and promoting robust angiogenesis in diabetic foot ulcers (<xref ref-type="bibr" rid="B26">Gong et al., 2025</xref>). Similarly, Li et al. reported a smart hydrogel dressing with dual-barrier drug delivery properties that enhanced healing of chronic infectious wounds (<xref ref-type="bibr" rid="B49">Li Y. et al., 2024</xref>). Moreover, He et al. developed a cascade-nanozyme-loaded hydrogel that facilitated revascularization and modulated macrophage phenotypes, thereby accelerating tissue regeneration (<xref ref-type="bibr" rid="B32">He et al., 2025</xref>). These findings, although outside the OA field, provide translational insights for designing multifunctional hydrogel scaffolds to improve cartilage repair and microenvironmental regulation in osteoarthritis.</p>
<p>Collectively, these findings highlight that scaffold-based nanotechnologies represent a convergence point of material science, molecular therapy, and regenerative medicine, and they are likely to play a pivotal role in the next-generation of clinically translatable OA treatments.</p>
</sec>
<sec id="s4-6">
<title>4.6 Lubricating functional nanoparticles</title>
<p>NPs exhibit unique mechanical and tribological properties, enabling them to enhance lubrication by modulating interfacial friction, infiltrating narrow gaps to form protective layers, and functioning as intermediate ball bearings between surfaces (<xref ref-type="bibr" rid="B1">Altman et al., 2015</xref>; <xref ref-type="bibr" rid="B46">Lawson et al., 2021b</xref>). Hyaluronic acid (HA), a key component of cartilage matrix and synovial fluid, possesses excellent viscoelasticity and strain-dependent properties, contributing to its distinctive hydrodynamic behavior and effective joint lubrication (<xref ref-type="bibr" rid="B57">Lu K.-H. et al., 2023</xref>). For decades, intra-articular injections of HA-based viscosupplements have been a widely adopted approach for managing osteoarthritis (OA)-related complications (<xref ref-type="bibr" rid="B27">Gonzales et al., 2023</xref>). The evidence-based clinical practice guidelines for knee OA, updated in both 2019 and 2023, endorse the use of hyaluronic acid (HA)-based viscosupplementation as a therapeutic approach (<xref ref-type="bibr" rid="B4">Barthold et al., 2024</xref>). Zheng et al. developed HA-MPC nanospheres, which demonstrated a 40% reduction in the coefficient of friction compared to HA alone (<xref ref-type="bibr" rid="B103">Zheng et al., 2022</xref>). These nanospheres can be administered via intra-articular injection to effectively treat OA by restoring joint lubrication (<xref ref-type="bibr" rid="B103">Zheng et al., 2022</xref>).</p>
</sec>
<sec id="s4-7">
<title>4.7 Nanoparticles for imaging diagnosis</title>
<p>In clinical practice, imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI) be typically employed to assess what constitute cartilage degeneration in OA patients (<xref ref-type="bibr" rid="B7">Braun and Gold, 2012</xref>; <xref ref-type="bibr" rid="B45">Lawson et al., 2021a</xref>). With continuous innovations in nanotechnology, researchers have explored NPs with unique physical properties to develop novel contrast agents that prolong <italic>in vivo</italic> retention, enhance sensitivity, reduce toxicity, and enable early OA diagnosis and progression monitoring (<xref ref-type="bibr" rid="B65">Mohammadinejad et al., 2020</xref>; <xref ref-type="bibr" rid="B102">Zhang et al., 2025</xref>). Zhang et al. designed a novel contrast agent platform utilizing cationic nanoparticles (NPs), which integrates cationic peptide carriers (CPCs) with multivalent poly (ethylene glycol)-modified avidin (mAv) NPs (<xref ref-type="bibr" rid="B100">Zhang C. et al., 2023</xref>). When combined with ioxaglate (IOX), this system effectively penetrates cartilage tissue via electrostatic interactions, significantly enhancing CT imaging (<xref ref-type="bibr" rid="B100">Zhang C. et al., 2023</xref>). In contrast to traditional IOX, this approach produces comparable CT signals at doses approximately 40 times lower, significantly minimizing toxicity concerns while offering a highly sensitive and safe method for early OA diagnosis and progression (<xref ref-type="bibr" rid="B100">Zhang C. et al., 2023</xref>; <xref ref-type="table" rid="T2">Table 2</xref>). In a separate study, Wu et al. engineered ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs) modified with the WYRGRL peptide ligand, designed to specifically target type II collagen within the cartilage matrix (<xref ref-type="bibr" rid="B91">Wu et al., 2023</xref>). As type II collagen degrades during OA progression, distinct MRI signal patterns emerge in OA subjects versus controls (<xref ref-type="bibr" rid="B91">Wu et al., 2023</xref>). This study introduces a promising approach for transporting nanoscale imaging agents to articular cartilage, which could facilitate the diagnosis of OA progression (<xref ref-type="bibr" rid="B91">Wu et al., 2023</xref>). In addition, a recent review summarized the applications of SPIONs in the diagnosis and treatment of bone and joint diseases, highlighting mechanisms, imaging sensitivity, biodistribution, and safety considerations (<xref ref-type="bibr" rid="B105">Zhu et al., 2024</xref>). PAI has emerged as a noninvasive imaging modality for OA diagnosis and monitoring (<xref ref-type="bibr" rid="B71">Park et al., 2024</xref>). Shen et al. engineered a photoacoustic probe (Au@PDA-WL NPs) designed to target type II collagen, consisting of gold NPs encapsulated in polydopamine (PDA) and functionalized with the WYRGRL peptide (<xref ref-type="bibr" rid="B76">Shen et al., 2023</xref>). Within this broader analytical framework, notably about these findings is that this innovation tends to suggest what be enhanced identification of early osteoarthritic alterations while seemingly creating novel opportunities for disease tracking and therapeutic investigations (<xref ref-type="bibr" rid="B76">Shen et al., 2023</xref>).</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Toxicity profiles of selected inorganic nanoparticles used in OA models.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Nanoparticle</th>
<th align="left">Dosage range</th>
<th align="left">Model system</th>
<th align="left">Route of administration</th>
<th align="left">Toxicological effects</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">TiO<sub>2</sub>
</td>
<td align="left">10&#x2013;100&#xa0;&#x3bc;g/mL</td>
<td align="left">Chondrocytes (<italic>in vitro</italic>)</td>
<td align="left">Direct culture</td>
<td align="left">ROS generation at &#x3e;50&#xa0;&#x3bc;g/mL</td>
</tr>
<tr>
<td align="left">CuO</td>
<td align="left">5&#x2013;50&#xa0;mg/kg</td>
<td align="left">Rat (<italic>in vivo</italic>)</td>
<td align="left">Intra-articular injection</td>
<td align="left">Dose-dependent inflammation</td>
</tr>
<tr>
<td align="left">CeO<sub>2</sub>
</td>
<td align="left">10&#x2013;200&#xa0;&#x3bc;g/mL</td>
<td align="left">RAW264.7 macrophages</td>
<td align="left">
<italic>In vitro</italic>
</td>
<td align="left">Low ROS and good biocompatibility</td>
</tr>
<tr>
<td align="left">Mg(OH)<sub>2</sub>
</td>
<td align="left">1&#x2013;10&#xa0;mM</td>
<td align="left">Human OA chondrocytes</td>
<td align="left">
<italic>In vitro</italic>
</td>
<td align="left">Safe below 5&#xa0;mM; cytotoxic at higher concentrations</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>What the evidence reveal, considering the nuanced nature of these findings, is that these studies provide evidence that may support the multifaceted potential of NPs in OA diagnosis and treatment, expanding therapeutic options and what offer new hope for improving patient outcomes in the majority of cases.</p>
</sec>
</sec>
<sec id="s5">
<title>5 Challenges and future directions</title>
<p>With the increasing aging and obese populations, the occurrence rate of OA is expected to rise progressively. At present, the majority of clinical approaches for managing OA aim to slow disease advancement, reduce pain, and enhance mobility. Nevertheless, the intricate molecular and cellular changes occurring in the cartilage of OA patients pose significant challenges, optimal therapeutic outcomes are difficult to achieve through conventional clinical approaches. Therefore, developing a treatment plan that enables long-term disease management and improves patient prognosis remains an urgent priority.</p>
<p>Progress in nanotechnology, combined with an enhanced comprehension of OA pathophysiology, has facilitated the application of nanoparticles&#x2019; distinctive characteristics. These advancements allow for sustained drug delivery, increased intra-articular drug persistence, and optimized therapeutic outcomes via functional modification approaches. These systems can also reduce therapeutic dosages, decrease administration frequency, enhance pharmacological effects, and minimize off-target toxicity. Various nanoparticles have been extensively explored for OA and other diseases, including chondroprotective therapies (<xref ref-type="bibr" rid="B93">Yang et al., 2020</xref>)and nanomaterial-based scaffolds for osteogenesis (<xref ref-type="bibr" rid="B61">Mahboudi et al., 2018</xref>). As a result, nanotechnology has become a highly promising field for creating novel therapeutic approaches to address OA.</p>
<p>Nevertheless, several technical challenges and limitations must be overcome before nanoparticles can be widely adopted for OA therapy. Liposomes are clinically well-studied but suffer from short circulation times. Polymeric nanoparticles provide superior sustained release but raise manufacturing and regulatory complexity. Inorganic nanoparticles offer multifunctional diagnostic and therapeutic capabilities, yet their long-term biosafety remains uncertain. Exosomes present excellent biological compatibility but face scalability and standardization challenges. These comparisons highlight that no single platform is universally optimal, and the maturity of each approach varies considerably. Key constraints include the scarcity of <italic>in vivo</italic> studies and the high production costs of NPs (<xref ref-type="bibr" rid="B28">Grayson and Brown, 2025</xref>). Additionally, synthetic nanomaterials are susceptible to the complex <italic>in vivo</italic> microenvironment, often failing to achieve their intended functionality, biocompatibility, and other design objectives (<xref ref-type="bibr" rid="B22">Farjadian et al., 2019</xref>). Furthermore, for nanoparticles to become a mainstream clinical treatment for OA, standardized evaluation systems for nanomedicines, clinical treatment guidelines, and regulatory frameworks must be established. Achieving these goals will require extensive, reliable data on safety and efficacy.</p>
<p>In summary, nanomaterials exhibit significant potential in the diagnosis and treatment of OA. They can be utilized not only for early OA diagnosis and monitoring disease progression but also for enhancing therapeutic efficacy and improving patients&#x2019; quality of life by targeting cartilage and synovium. Looking ahead, we anticipate that future investigations will increasingly focus on: (1) intelligent and multi-responsive drug delivery systems capable of dynamic, on-demand release under specific pathological stimuli; (2) precision and personalized nanomedicine tailored to individual OA phenotypes and patient-specific joint microenvironments; (3) biomimetic nanomaterials that integrate with biological tissues to improve safety and long-term biocompatibility; and (4) interdisciplinary strategies that combine nanotechnology with gene therapy, stem cell therapy, and regenerative medicine. Importantly, the establishment of standardized regulatory guidelines and robust evaluation criteria for nanomedicines will be crucial to facilitate clinical translation. With these directions, nanotechnology is expected to reshape OA management by enabling more precise, safer, and effective treatment paradigms&#x201d;.</p>
</sec>
</body>
<back>
<sec sec-type="author-contributions" id="s6">
<title>Author contributions</title>
<p>XL: Writing &#x2013; original draft, Writing &#x2013; review and editing. ZS: Writing &#x2013; original draft, Writing &#x2013; review and editing. SZ: Methodology, Supervision, Writing &#x2013; review and editing. YC: Writing &#x2013; review and editing. XL: Funding acquisition, Project administration, Resources, Supervision, Writing &#x2013; review and editing. XH: Funding acquisition, Project administration, Resources, Supervision, Writing &#x2013; review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s7">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research and/or publication of this article. This study was carried out within the scope of: 1) Shaoxing Municipal Health and Medical Science and Technology Program Project (2024SKY014), 2) Shaoxing Health Science and Technology Plan Project (2023SKY013).</p>
</sec>
<sec sec-type="COI-statement" id="s8">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
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<title>Generative AI statement</title>
<p>The author(s) declare that no Generative AI was used in the creation of this manuscript.</p>
<p>Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.</p>
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<title>Publisher&#x2019;s note</title>
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