Muscle-Targeted Nanocomposite Therapy Alleviates Age-Related Sarcopenia via Antioxidant and Metabolic Reprogramming

Sarcopenia, a progressive skeletal muscle disorder marked by loss of mass and function, presents growing societal challenges due to limited therapeutic options. Here, we identify mitochondrial dysfunction and oxidative stress as central drivers of sarcopenia through integrated bioinformatics and clinical validation. To address this pathophysiology, we engineer a muscle-targeted nanocomposite (BP-PEG-MOTS-c, BM) combining mitochondrial-derived peptide MOTS-c with antioxidant black phosphorus nanosheets (BP). BM exhibits dual functionality: MOTS-c restores mitochondrial function, while BP synergistically amplifies ROS scavenging capacity. In cellular and murine models with age-related sarcopenia, BM treatment alleviates muscle dysfunction and muscle loss, concurrently normalizing mitochondrial function and reducing lipid peroxidation. Mechanistic profiling via RNA-seq reveals BM's activation of PI3K/AKT/Nrf2 and suppression of ROS/p38 MAPK signaling pathway, mediating antioxidant responses and maintenance of mitochondrial homeostasis. The nanocomposite demonstrats superior biocompatibility in toxicity assays, outperforming conventional delivery systems. Our findings establish that BM has been established as a promising mitochondrial redox modulator with translational potential for sarcopenia and related age-associated pathologies.