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With no disease\u2010modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Rapamycin\u2010loaded in poly(lactic\u2010co\u2010glycolic acid) microparticles (RMPs) induced autophagy, prevented senescence, and sustained sulphated glycosaminoglycans production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35\u2009days) in mice joints. Intra\u2010articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery\u2010induced OA when administered as a prophylactic or therapeutic regimen. 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