Engineering Principles of Extracellular Vesicles for Central Nervous System Therapies.

Extracellular Vesicles (EVs) are active mediators of intercellular signaling in the Central Nervous System (CNS), operating alongside synaptic transmission as an extra form of wireless communication between neurons and other brain cell types. Their biocompatibility positions them as promising carriers for neurobiological therapeutics; however, translation hinges on clarifying when and how EVs traverse the Blood-Brain Barrier (BBB) and how their design can be aligned to pathophysiology. We synthesize evidence for BBB transport from in vitro models and in vivo visualization and functional studies and build on this foundation by outlining engineering strategies for CNS tropism both to the brain and within it. Across these areas, current advances remain largely siloed despite clear mechanistic interdependence, underscoring the need for standardized frameworks that integrate barrier biology, engineering design, and disease context. We argue that progress now depends on two fronts: developing preclinical models that accurately capture mechanisms governing bidirectional EV transport through the BBB and aligning vesicle design and delivery parameters with those mechanisms. Achieving this will require closer integration with biomarker discovery and greater standardization across preclinical workflows. Together, these steps chart a path from proof of concept to clinically adaptable EV therapeutics for CNS disease.