Energy-replenishing, mitochondria-targeted hydrogel microspheres mitigate sarcopenia via cellular senescence amelioration.

Sarcopenia is a degenerative skeletal muscle disorder closely associated with aging, characterized by the gradual loss of muscle mass and function, which severely impacts the quality of life in the elderly. In general, the severity of sarcopenia varies significantly among different patients and across different muscle groups, which increases the complexity and challenge of sarcopenia treatment. Based on the core pathological mechanism of sarcopenia, namely the deficiency of Nicotinamide adenine dinucleotide (NAD(+)) induced mitochondrial dysfunction, this study has developed a novel Energy-replenishing hydrogel microsphere (NMN@Lipo-s@AHM) for the targeted delivery of Nicotinamide Mononucleotide (NMN) to muscle cells through local injection. The stability of NMN was enhanced through liposomal encapsulation, peptide SS-31 was applied for mitochondrial targeting, and sustained local releasing was achieved via aldehyde hyaluronic acid methacrylate hydrogel microspheres (AHM). In vitro and in vivo experiments demonstrated that the Energy-replenishing hydrogel microspheres significantly alleviated dexamethasone-induced mitochondrial dysfunction and senescent phenotypes in muscle cells. Transcriptomic and proteomic analyses revealed that the hydrogel microsphere regulates mitochondrial function by activating the "AMPK-SIRT1-PGC1α" signaling pathway, thereby synergistically improving mitochondrial energy metabolism and cellular senescence. This study not only provides an efficient targeted delivery strategy for NADsupplementation but also offers new directions for the mechanistic research and clinical intervention of sarcopenia.