Approaches to Enhance the Regenerative Potential of MSC-derived Extracellular Vesicles (MSCEV): A Promising Cell-free Therapy for Osteoarthritis.

Osteoarthritis therapy remains a big challenge since no causative treatment options are available so far. Current preclinical studies report that extracellular vesicles derived from mesenchymal stem cells have high potential to change disease evolution and protect the cartilage matrix. Extracellular vesicles are diverse nanoscale, membrane-bound particles that mediate and regulate intercellular communication. Their therapeutic efficacy in terms of clinical translation is highly dependent on the status of mesenchymal stem cells. Mesenchymal stem cells have been shown to respond to different aspects of the injury microenvironment. Recent research has explored the use of diverse stimuli to enhance stem cell secretion and improve the biological activity of released extracellular vesicles. The most common approach to influence the profile and biological activities of mesenchymal stem cell-derived factors is to recreate a pro-inflammatory environment mimicking an in vivo pathological setting, but other promising methods also deserve to be investigated. This narrative review summarizes and discusses recent strategies aimed at enhancing the regenerative and supportive effect of mesenchymal stem cell-derived extracellular vesicles by improving the secretion capacity of cells via different stimulation, with a focus on the development and clinical translation of engineered vesicles for joint disorders. Relevant literature was identified through searches of PubMed and Web of Science for peer-reviewed articles published between 2018 and 2026, with priority given to experimental, translational, and clinical studies investigating MSCEVs in OA and approaches for modifying their production, cargo, targeting, or delivery.