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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. 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