Dual-targeted exercise mimetic extracellular vesicles regulate the muscle-bone crosstalk to treat osteosarcopenia

Clinically, the co-presentation of osteoporosis and sarcopenia often occurs in the same individuals, termed osteosarcopenia (OSP). Although OSP has high incidence and causes significant morbidity, there are no effective treatments concurrently re-establishing bone and muscle mass. Recent researches highlight the existence of inter-organ communication between bone and muscle, inspiring exercise-mimetic therapies that utilizing exercise-inducible myokines and osteokines beyond their original organs. This study proposes the pioneering concept of exercise mimetic extracellular vesicles (EMEVs) for the treatment of OSP. The EMEVs are produced by human induced pluripotent stem cells-derived myotubes and stimulated with mechanical strain to mimic exercise. These EMEVs were found to contain abundant exercise-inducible cargos, especially irisin, with beneficial effects including promoting the proliferation of muscle stem cells, extending the lifespan of myotubes and converting their cytokine profile, and facilitating osteogenic differentiation in vitro . Subsequently, dual-targeted EMEVs (DT-EMEVs) were constructed by modifying EMEVs with bone-targeting and muscle-targeting peptides, which exhibited organ-specific distribution in vivo . In aged OSP murine models, DT-EMEVs effectively recovered both bone and muscle mass, enhanced exercise performance, and improved bone mechanical strength. Beyond targeted and effective treatment of OSP, DT-EMEVs may inspire new paradigms in the managing other musculoskeletal disorders and developing exercise mimetic therapies.