Engineered Exosomal miR‐146a‐5p Reprograms BMSC Fate and Restores Mitochondrial Homeostasis in Glucocorticoid‐Induced Osteonecrosis of Femoral Head

ABSTRACT Glucocorticoid (GC)‐induced osteonecrosis of the femoral head (ONFH) involves stem cell senescence, mitochondrial dysfunction, and impaired bone regeneration. However, the molecular basis linking GC stress to bone marrow stromal cell (BMSC) dysfunction remains unclear. Here, we identify miR‐146a‐5p as a key regulator of BMSC fate under GC exposure, through comprehensive transcriptomic analysis of clinical bone marrow samples from GC‐induced ONFH patients. Exosomes engineered to deliver miR‐146a‐5p restored mitochondrial membrane potential, suppressed oxidative stress, and reactivated mitophagy by targeting the TRAF6‐NF‐κB axis. These exosomes reversed GC‐induced senescence and enhanced osteogenic and angiogenic capacity in vitro and in vivo. In a rat ONFH model, intraosseous delivery of miR‐146a‐5p exosomes improved trabecular structure and vascularization. Single‐cell RNA‐seq revealed a shift toward osteogenic and immunomodulatory BMSC subtypes. Our findings demonstrate that miR‐146a‐5p‐engineered exosomes rejuvenate skeletal regeneration by restoring mitochondrial homeostasis and inflammatory balance, offering a promising cell‐free therapy for GC‐associated ONFH.