Advances in the application of mesenchymal stem cells-derived extracellular vesicles in “enthesis” healing

The enthesis, the site where tendons or ligaments attach to bone, serves as a transitional interface between soft and hard tissues. Owing to its complex histological structure and unique physiological characteristics, repair of this region after injury remains a significant clinical challenge. Traditional treatments for common enthesis injuries involving the anterior cruciate ligament, rotator cuff, and Achilles tendon have shown limited efficacy and often fail to achieve true functional tissue regeneration. In recent years, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted considerable attention because of their biological functions, including regulation of the tissue microenvironment, promotion of tissue repair, and targeted drug delivery. As the primary paracrine mediators of MSCs, MSC-EVs carry bioactive substances, including proteins, nucleic acids, and lipids, similar to those of their parent cells. They offer several advantages, including nanoscale size, low immunogenicity, immune-evasion capacity, prolonged circulation, and the ability to mediate intercellular communication. The therapeutic potential of MSC-EVs in sports-related injuries has been widely investigated. In this review, we systematically summarize the progress in applying MSC-EVs, including native, engineered, and biomaterial-assisted vesicles, to promote enthesis healing. We further discuss the advantages of engineering strategies and biomaterial-assisted approaches, as well as their potential mechanisms of action. Finally, we propose future research directions to provide useful references and insights for further studies in this field.