Vesicular Communication in the Bone–Muscle Unit: Physiological Functions, Aging, and Therapeutic Potential

Extracellular vesicles (EVs) have emerged as fundamental pillars of intercellular communication, acting as primary mediators of the bidirectional biochemical crosstalk within the integrated bone-muscle unit. This review provides a comprehensive synthesis of EV-mediated signaling across the bone-muscle axis, offering a side-by-side mapping of vesicular biogenesis, cargo composition, and functional roles in both tissues. Under physiological conditions, skeletal muscle- and bone-derived EVs orchestrate tissue homeostasis, adaptations to physical exercise, myogenesis, and bone remodeling by transferring unique molecular cargos of proteins and specific microRNAs. However, aging induces a profound remodeling of the EV secretome toward a senescent profile characterized by harmful vesicular factors. This dysfunctional vesicular signaling impairs both muscle regeneration and osteogenesis, directly contributing to the pathogenesis of interconnected age-related disorders like sarcopenia, osteoporosis, and osteosarcopenia. Concurrently, circulating EVs represent valuable, minimally invasive biomarkers for early diagnosis. On the therapeutic front, this review critically evaluates emerging EV-based approaches, utilizing mesenchymal stem cell-derived, bioengineered, or biomaterial-incorporated EVs, offering promising, low-immunogenic alternatives to cell transplantation to enhance musculoskeletal tissue repair and restore bone-muscle homeostasis. Despite persisting technical challenges regarding large-scale production and standardization, targeting or leveraging EV-mediated communication represents one of the most innovative and revolutionary strategies to counteract age-related musculoskeletal decline. By unifying physiological mechanisms, age-related molecular reprogramming, and therapeutic engineering across both muscle and bone into a single narrative, this review provides a comprehensive framework to guide future research and clinical translation in musculoskeletal health.