Skeletal muscle‑derived extracellular vesicles in multi‑organ degenerative disease: Mechanisms and therapeutic delivery perspectives (Review)

Multi-organ degenerative diseases are ageassociated or chronic disorders marked by progressive tissue deterioration, impaired repair and functional decline, with representative conditions including sarcopenia, osteoporosis, osteoarthritis, neurodegenerative or ischemia-associated neurological disorders, heart failure, chronic kidney disease and diabetes-associated tissue dysfunction.Their frequent coexistence in aging populations limits the effectiveness of therapeutic strategies directed at a single organ or pathway.Extracellular vesicles (EVs) are lipid bilayer-enclosed particles that shuttle proteins, lipids, metabolites and regulatory RNAs between cells and tissue.As a highly metabolic and secretory tissue, skeletal muscle releases skeletal muscle-derived EVs (SkM-EVs) that may carry muscle-enriched microRNAs, together with other regulatory cargo molecules involved in local tissue remodeling and systemic signaling.SkM-EVs have therefore been proposed as mediators of muscle-centered cross-organ communication and potential delivery vehicles for molecular intervention, although therapeutic evidence remains largely preclinical.The present review examines the biological functions of SkM-EVs, their regulation by exercise, aging and metabolic stress and their potential involvement in multi-organ degenerative diseases.The present study aimed to discuss engineering strategies for SkM-EVs, including cargo loading, surface modification and targeted delivery, with particular attention to controversies, methodological limitations, quality control requirements and barriers to clinical translation. Contents1. Introduction 2. Biogenesis, structural features and functional cargo of SkM-EVs 3. SkM-EVs in local muscle remodeling and musculoskeletal crosstalk 4. SkM-EVs in neuromuscular and multi-organ communication 5. Context-dependent remodeling of SkM-EV release and cargo profiles 6. Therapeutic targets and technological frontiers for SkM-EV-based intervention 7. Discussion 8. Conclusion