Mesenchymal stem cell-derived extracellular vesicles for dry eye disease: principles, progress, and challenges.

Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by disruption of tear film and/or ocular surface homeostasis that represents a significant global public health concern. This review summarizes the pathogenesis of DED, with particular emphasis on the central role of ocular surface inflammation. It further comprehensively evaluates the therapeutic rationale, preclinical advances, and translational challenges associated with mesenchymal stem cell-derived extracellular vesicle (MSC-EV) therapy for DED. MSC-EVs exhibit numerous properties, including anti-inflammatory, immunomodulatory, reparative, and regenerative effects, and offer key advantages such as a cell-free nature, low immunogenicity, minimal tumorigenic risk, high stability, and suitability for topical administration. Through advanced strategies such as cargo engineering, hybrid design, biomaterial-assisted delivery, and genetic engineering, the therapeutic performance of MSC-EVs can be further optimized, enabling targeted delivery, improved retention and bioavailability, and precise immunomodulation. In addition, three-dimensional ocular surface and ex vivo models help overcome the limitations of traditional animal models in replicating human ocular physiology. Among available sources, umbilical cord-derived MSC-EVs represent one of the most promising candidates for clinical translation. Despite these advances, several challenges remain, including ocular-specific anatomical and physiological barriers, limited pharmacological characterization, lack of standardized large-scale production and storage protocols, incomplete toxicological and microbiological safety evaluation, and the absence of a unified regulatory framework. Overall, MSC-EVs represent a potentially transformative therapeutic strategy for the management of refractory DED. However, as most current evidence remains preclinical, further validation in human-relevant models and clinical studies is essential before definitive conclusions can be drawn.