Smart Nanodelivery Systems for Immunometabolic Modulation in Osteoarthritis

Qirui Zhao; Zhewen Mi; Shuya Liu; Shijun Liang; Linjia Peng; Zixuan Gao; Jiaming Li; Xiaoqing Lu; Zhiguang Ren; Yongjie Wan; Shengsheng Cui; Longlong Lu; Xiaoyang Gao; Tao Wang; Hui Liang; Furong Tian; Jesus M de la Fuente; Chong Xiang; Luyi Sun; Lichen Xiang; Daxiang Cui

doi:10.1002/exp2.70185

Exploration ›› 2026, Vol. 6 ›› Issue (3) :70185 DOI: 10.1002/exp2.70185

REVIEW

Smart Nanodelivery Systems for Immunometabolic Modulation in Osteoarthritis

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¹. Department of Orthopedics, The First Affiliated Hospital of Henan University, Henan University Kaifeng, Kaifeng, China

². Henan Province Engineering Technology Research Center of Intelligent Diagnosis and Treatment, The First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, China

³. Department of Orthopedics, Kaifeng Traditional Chinese Medicine Hospital, Kaifeng, China

⁴. Key Laboratory of Zhongzhou, Henan Province, Kaifeng, China

⁵. Nanolab Research Centre of Technology University Dublin, Dublin, Ireland

⁶. Institute of Nano Biomedicine and Engineering, School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai JiaoTong University, Shanghai, China

⁷. Instituto De Nanociencia y Materiales De Aragon, CSIC-University of Zaragoza and CIBER-BBN, Zaragoza, Spain

⁸. Polymer Program, Institute of Materials Science and Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, USA

⁹. State Key Laboratory of Tribology in Advanced Equipment (SKLT), Tsinghua University, Beijing, China

¹⁰. Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health, Bethesda, USA

luyi.sun@uconn.edu

xlc@henu.edu.cn

dxcui@sjtu.edu.cn

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Abstract

Osteoarthritis (OA) is a chronic degenerative joint disease characterised primarily by immunometabolic disorders within the synovium-cartilage axis. Conventional therapies are limited by poor drug accumulation and nonspecific distribution at lesion sites, resulting in suboptimal and short-lived efficacy. In recent years, smart responsive nanodelivery systems (SRNSs) have demonstrated considerable potential for OA treatment. This review systematically summarises the major responsive mechanisms of SRNSs—such as pH, reactive oxygen species, enzymes and temperature—and their corresponding targeting strategies, including hyaluronic acid (HA)-cluster of differentiation 44, arginine-glycine-aspartic acid-collagen II and immune ligand recognition. The dual modulatory roles of SRNSs in the synovium-cartilage axis are highlighted. By analysing validation evidence from representative material systems—such as zeolitic imidazolate framework-8, poly(lactic-co-glycolic acid) and liposomes—in animal models, we delineate the synergistic mechanisms of SRNSs in inflammation suppression, metabolic remodelling and tissue regeneration. In the discussion section, we further explore key challenges for SRNSs, including biosafety concerns, lesion heterogeneity, manufacturing processes and regulatory standards. Potential strategies—such as biomimetic membrane camouflage, multi-omics-based stratification, artificial intelligence (AI) simulation and virtual clinical trials—are also proposed. Additionally, by comparing SRNSs with gene therapy, cell-penetrating peptides and exosome-based delivery, this review suggests that future OA therapies may evolve toward hybrid platforms integrating materials, biological systems and gene-based interventions. Looking ahead, smart systems endowed with self-feedback, self-evolution and visualisation capabilities are expected to move OA treatment toward a new era of personalised, adaptive and multidimensional precision interventions.

Keywords

immunometabolic remodelling / osteoarthritis / small-molecule intervention / smart responsive nanocapsules / synovium-cartilage axis / targeted delivery systems

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Qirui Zhao, Zhewen Mi, Shuya Liu, Shijun Liang, Linjia Peng, Zixuan Gao, Jiaming Li, Xiaoqing Lu, Zhiguang Ren, Yongjie Wan, Shengsheng Cui, Longlong Lu, Xiaoyang Gao, Tao Wang, Hui Liang, Furong Tian, Jesus M de la Fuente, Chong Xiang, Luyi Sun, Lichen Xiang, Daxiang Cui. Smart Nanodelivery Systems for Immunometabolic Modulation in Osteoarthritis. Exploration, 2026, 6 (3) : 70185 DOI:10.1002/exp2.70185

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