Extracellular Vesicle Communication in the Central Nervous System: Mechanisms, Disease States, and Therapeutic Opportunities

Extracellular vesicles (EVs) are increasingly recognized as regulated mediators of intercellular communication in the central nervous system (CNS), transferring proteins, lipids, metabolites, and nucleic acids among neurons, glia, and other cells. EV communication comprises a complex integrated pathway that includes vesicle biogenesis, selective cargo sorting, secretion, extracellular transport, target-cell recognition, uptake, intracellular trafficking, functional cargo delivery, and recipient-cell responses. These processes are controlled by membrane trafficking machinery, cytoskeletal dynamics, lipid metabolism, calcium signaling, and the endosomal–lysosomal system and are further shaped by the physiological and pathophysiological states of donor and recipient cells. Genetic variation, proteotoxic stress, inflammation, metabolic and redox alterations, neuronal activity, and endolysosomal dysfunction can therefore affect multiple stages of the EV communication pathway in neurodevelopmental and neurodegenerative disorders. EV alterations reflect dynamic states rather than fixed disease signatures, with effects depending on cellular origin, EV subtype, anatomical context, developmental or disease state, and recipient-cell competence. This review examines CNS EV physiology and proposes a state-dependent framework for biomarkers and therapies, distinguishing EV detection from functional cargo delivery, cross-sectional associations from longitudinal progression, and cellular uptake from intracellular target engagement.