SHED-derived exosomes ameliorate age-related osteoporosis by activating mitophagy in senescent bone marrow mesenchymal stem cells

AIM: This study aims to explore the therapeutic efficacy of stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-Exo) in age-related osteoporosis (OP) and clarify its mechanism via mitophagy activation in senescent bone marrow mesenchymal stem cells (BMSCs). METHODS: SHED-Exo were isolated, characterized and proteomically profiled. In vitro, H₂O₂-induced senescent bone marrow mesenchymal stem cells (BMSCs) were treated with SHED-Exo, with mitophagy modulators used for mechanistic validation. In vivo, SHED-Exo were systemically administered to aged osteoporotic mice, assessing biodistribution, safety and therapeutic effects via micro-computed tomography, and molecular analyses of bone tissue/BMSCs. RESULTS: SHED-Exo possessed canonical exosomal properties and were enriched in osteogenic/mitophagic proteins. In vitro, SHED-Exo restored mitochondrial function, activated mitophagy and enhanced osteogenic differentiation of senescent BMSCs. In vivo, SHED-Exo showed no organ toxicity and effectively ameliorated bone loss by upregulating mitophagic/osteogenic markers in aged osteoporotic mice. CONCLUSION: SHED-Exo ameliorate age-related OP by activating mitophagy in senescent BMSCs, serving as a novel translational nanotherapeutic for age-related bone disorders.