Advancing Sports Injury Treatment Through Cell-Free MSC-Based Therapies: A Narrative Review

Background: Sports-related musculoskeletal injuries, including tendon, ligament, muscle, and cartilage damage, often heal slowly and incompletely. Current treatments may not fully restore tissue function, necessitating regenerative therapies. Objective: This study was conducted to review the therapeutic potential of stem cell-derived extracellular vesicles (EVs) and conditioned medium (CM) as cell-free approaches to treating musculoskeletal injuries in sports medicine. Methods: A narrative review of preclinical and early clinical studies investigating the biological mechanisms and regenerative effects of mesenchymal stem/stromal cell (MSC)-derived EVs and CMs published between 2019 and 2026 was performed by searching Scopus, PubMed, Web of Science, and Google scholar. Results: EVs and CMs contain bioactive molecules, including microRNAs, cytokines, and growth factors, that modulate inflammation, promote tissue repair, enhance angiogenesis, and support extracellular matrix remodeling. Preclinical studies demonstrate improved healing of tendons, ligaments, muscles, and cartilage, while early clinical evidence suggests favorable safety and promising therapeutic outcomes. However, the variety of MSC sources, EV separation methods, characterization procedures, and treatment protocols present major challenges in determining the reliability and therapeutic efficacy of these therapies. Notably, the number of clinical studies on EV and CMs is still limited, and most of the available studies are in vitro studies. Conclusions: MSC-derived EVs and CMs represent promising cell-free regenerative therapies for sports-related musculoskeletal injuries. The available evidence, which demonstrates their ability to enhance healing while avoiding the challenges associated with cell-based therapies, highlights their translational potential. However, most of the studies that are now available are preclinical or early-stage clinical studies, and there is still a limited number of clinical trials. Further well-designed clinical studies are needed to establish standardized protocols and confirm long-term safety.