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However, how to make the regulatory means match the pathological mechanical microenvironment\u2010dependent activation of TGF\u2010\u03b21 to promote lesion repair still faces challenges. In this study, based on force\u2010charge conversion technology,\u00a0we developed the stress\u2010responsive charge\u2010reversal hydrogel microsphere system. Weakly cross\u2010linked disulfide bonds in the microfluidic\u2010synthesized microspheres break under mechanical stress, interacting with charge\u2010reversal messenger to induce nanoparticle charge reversal\u00a0(negative to positive). This mode is in line with the activation mechanism of TGF\u2010\u03b21 in the mechanical microenvironment, which can match the appropriate regulatory intensity and thus achieve high efficiency and low toxicity in OA treatment. Experimental results show that this hydrogel microsphere system has a 41.96% improvement in the repair effect of OA cartilage lesions compared to traditional microspheres, and more importantly, the impact on healthy cartilage is reduced by 96.89%. This study provides a new idea for the development of biomaterial regulatory systems that match the pathological microenvironment.<\/jats:p>","DOI":"10.1002\/exp.20250363","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T03:56:35Z","timestamp":1781063795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Matching TGF\u2010\u03b21 Activation With Stress\u2010Responsive Charge\u2010Reversal Hydrogel Microspheres for the Treatment of Osteoarthritis"],"prefix":"10.1002","volume":"6","author":[{"given":"Feng","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province The Second Affiliated Hospital Zhejiang University School of Medicine Orthopedics Research Institute of Zhejiang University Clinical Research Center of Motor System Disease of Zhejiang Province  Hangzhou P. 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