Brain targeting and trafficking of extracellular vesicles in central nervous system diseases: a therapeutic roadmap.

Extracellular vesicles (EVs) mediate intercellular signaling in the central nervous system (CNS) by transferring lipids, proteins, and nucleic acids among neurons, glia, endothelium, and immune cells. Brain targeting depends on a linked sequence: EV ligands and adsorbed protein coronas engage receptor modules, select endocytic routes, determine intracellular fate, and define the therapeutic readouts. These fates include lysosomal degradation, recycling, rare cytosolic delivery, or transport across the blood-brain barrier (BBB). In disease, the same pathways can disseminate proteopathic seeds and amplify neuroinflammation. Heparan sulfate proteoglycans (HSPGs) and LDL receptor family members, including low-density lipoprotein receptor-related protein 1 (LRP1), regulate tau, α-synuclein, and amyloid-β handling. Phosphatidylserine readers and complement shape myeloid sink capture and inflammatory output. Integrin, tetraspanin, and ICAM-1 nanoclusters influence avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake, motivating engineered ligands such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders. However, endosomal escape remains a major kinetic barrier to nucleic acid delivery. We synthesize these principles across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease, and outline design and assay standards needed to translate EV biology into safe, manufacturable CNS therapeutics.