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However, the molecular basis linking GC stress to bone marrow stromal cell (BMSC) dysfunction remains unclear. Here, we identify miR\u2010146a\u20105p as a key regulator of BMSC fate under GC exposure, through comprehensive transcriptomic analysis of clinical bone marrow samples from GC\u2010induced ONFH patients. Exosomes engineered to deliver miR\u2010146a\u20105p restored mitochondrial membrane potential, suppressed oxidative stress, and reactivated mitophagy by targeting the TRAF6\u2010NF\u2010\u03baB axis. These exosomes reversed GC\u2010induced senescence and enhanced osteogenic and angiogenic capacity in vitro and in vivo. In a rat ONFH model, intraosseous delivery of miR\u2010146a\u20105p exosomes improved trabecular structure and vascularization. Single\u2010cell RNA\u2010seq revealed a shift toward osteogenic and immunomodulatory BMSC subtypes. Our findings demonstrate that miR\u2010146a\u20105p\u2010engineered exosomes rejuvenate skeletal regeneration by restoring mitochondrial homeostasis and inflammatory balance, offering a promising cell\u2010free therapy for GC\u2010associated ONFH.<\/jats:p>","DOI":"10.1002\/advs.75897","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T15:29:09Z","timestamp":1781537349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineered Exosomal miR\u2010146a\u20105p Reprograms BMSC Fate and Restores Mitochondrial Homeostasis in Glucocorticoid\u2010Induced Osteonecrosis of Femoral Head"],"prefix":"10.1002","volume":"13","author":[{"given":"Zehui","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union 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