Engineering small extracellular vesicles: Unlocking the brain’s secret passage for central nervous system therapies

Small extracellular vesicles (sEVs), naturally occurring extracellular vesicles, play a pivotal role in intercellular communication and have gained significant attention for their potential in treating central nervous system (CNS) diseases. Due to their ability to cross the blood-brain barrier (BBB) and deliver therapeutic cargo, sEVs are considered a promising vehicle for targeted drug delivery in CNS disorders. Recent advancements in sEVs engineering—such as surface modifications, genetic alterations, and cargo optimization—have substantially enhanced their specificity and therapeutic efficacy. This review examines the relevance of endogenous sEVs in CNS and highlights recent developments in sEVs engineering and cargo optimization. We then discuss strategies for targeting specific brain cells, including neurons, microglia, and endothelial cells. Although clinical applications show promising potential, they remain in early stages, with challenges including large-scale production, precise tracking, standardized preparation, and efficient long-distance targeting. Further research into the cellular mechanisms of sEVs -mediated delivery and the functional differences between sEVs derived from various cell types is crucial for advancing their clinical translation in CNS therapies.