Extracellular matrix-mimetic hydrogel encapsulating myoblast exosomes attenuates muscle atrophy by targeting Nrf2-mitochondrial axis

The pathogenesis of sarcopenia, a geriatric syndrome associated with chronic glucocorticoid exposure, involves redox homeostasis dysregulation of skeletal muscle. There is an urgent need for targeted therapeutic strategies. In this study, we developed a thermosensitive hydrogel composed of skeletal muscle-derived decellularized extracellular matrix, chitosan, and β-glycerophosphate. This multifunctional platform was co-encapsulated with a nuclear factor erythroid 2-related factor 2 (Nrf2) agonist (bardoxolone) and myoblast-derived exosomes to synergistically enhance muscle regeneration. The injectable hydrogel exhibited rapid sol-gel transition at 37 °C and sustained bardoxolone release kinetics. In dexamethasone (Dex)-induced C2C12 myoblasts, the hydrogel effectively normalized atrophic markers (muscle-specific RING finger protein 1, muscle atrophy F-box protein), while upregulating myogenic factors (myoblast determination protein 1, myosin heavy chain, myosin heavy chain 7, and myogenin). Intramuscular administration of the hydrogel in Dex-treated mice ameliorated sarcopenic manifestations through enhanced skeletal muscle mass, grip strength, weight-loaded swimming time, rotating rod time, and myofiber cross-sectional area. Mechanistically, the hydrogel restored mitochondrial impairment in Dex-treated myoblasts through Nrf2 pathway activation, evidenced by upregulated nuclear Nrf2, translocase of outer mitochondrial membrane 20, voltage dependent anion channel 1, and recovered oxygen consumption rate. Crucially, complete therapeutic efficacy ablation in both in vitro and in vivo Nrf2-knockout models confirmed Nrf2 as the central regulatory hub. This hydrogel integrates extracellular matrix-mimetic architecture, controlled molecular release kinetics, and exosome-mediated cytoprotection, establishing a therapeutic strategy for sarcopenia management.