Objective  To summarize the research progress on immune microenvironment imbalance and targeted interventions in osteoarthritis comorbid with diabetes mellitus, so as to provide a reference for the development of disease-modifying therapies and individualized local drug-delivery strategies for this comorbid population. Methods  Relevant domestic and international studies published in recent years were reviewed. Focusing on the “oxidative stress-immune interaction” axis, the major alterations and cellular network characteristics of the immune microenvironment in osteoarthritis comorbid with diabetes mellitus were summarized, with emphasis on microenvironment-targeted intervention strategies, including small-molecule drug repurposing, nanodelivery systems, exosome/nucleic acid-based therapeutics, and injectable biomaterials. Challenges and prospects related to stratified diagnosis and treatment, efficacy endpoints, and long-term safety in clinical translation were also discussed. Results  The core pathological basis of osteoarthritis comorbid with diabetes mellitus involves hyperglycemia-induced oxidative stress and immunometabolic reprogramming. Through mechanisms such as the accumulation of advanced glycation end products, lipotoxicity, mitochondrial dysfunction, and abnormalities in the gut-joint axis, these changes promote persistent synovitis, extracellular matrix degradation, pain sensitization, and structural joint damage. Immune microenvironment imbalance is mainly characterized by pro-inflammatory polarization of synovial macrophages with impaired efferocytosis, T helper 17 cells/regulatory T cells imbalance, reduced immunomodulatory capacity of mesenchymal stem cells and their exosomes, and senescence-associated immune remodeling in bone marrow lesion areas. Based on these mechanisms, targeted intervention strategies, including small-molecule drug repurposing, nanodelivery systems, exosome/nucleic acid-based therapeutics, and injectable biomaterials, have shown promising application prospects. However, their clinical translation still faces challenges, such as insufficient stratified diagnosis and treatment, inadequate efficacy evaluation systems, and limited long-term safety evidence. Conclusion The development and progression of osteoarthritis comorbid with diabetes mellitus are closely associated with the persistent interplay among metabolic abnormalities, oxidative stress, and immune microenvironment imbalance. Targeted interventions based on modulation of the local joint microenvironment may relieve pain, improve joint function, and delay the progression of structural joint damage, thereby providing new insights into disease-modifying therapy. Future studies should further refine stratified diagnostic and therapeutic strategies, optimize biomarker selection and delivery platform design, and strengthen long-term safety evaluation to facilitate clinical translation of these strategies.

Citation： SUN Yuanlin, YANG Yunkang. Research progress on immune microenvironment imbalance and targeted interventions in osteoarthritis comorbid with diabetes mellitus. Chinese Journal of Reparative and Reconstructive Surgery, 2026, 40(7): 1149-1156. doi: 10.7507/1002-1892.202601112 Copy

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