Extracellular Vesicles: Brain Targeting and Trafficking Principles Charted for CNS Disease Therapeutics

The blood-brain barrier (BBB) presents a formidable challenge for delivering therapeutic agents to the central nervous system (CNS), severely limiting treatment options for neurodegenerative diseases and brain cancers. Traditional small molecule drugs often lack specificity or fail to cross the BBB effectively, while larger biologics face even greater hurdles. Extracellular vesicles (EVs), lipid bilayer-enclosed nanoparticles, have emerged as promising natural carriers for intercellular communication, capable of transferring lipids, proteins, and nucleic acids. Understanding their intrinsic brain-targeting mechanisms is crucial to harness their therapeutic potential and overcome current delivery limitations.

Researchers conducted a comprehensive review synthesizing current literature on extracellular vesicles (EVs) to delineate mechanisms of brain targeting and trafficking in various central nervous system (CNS) diseases. They systematically analyzed how EV surface ligands, adsorbed protein coronas, and specific receptor modules dictate endocytic routes, intracellular fate, and transport across the blood-brain barrier (BBB). The review integrated findings across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, glioblastoma, and demyelinating disease to identify common principles and challenges. The authors also outlined design and assay standards necessary for translating EV biology into safe and manufacturable CNS therapeutics.

The review identified a linked sequence of events governing EV brain targeting: surface ligands and protein coronas engage specific receptor modules, which then select endocytic routes, determine intracellular fate, and define therapeutic readouts. Key receptors involved include heparan sulfate proteoglycans (HSPGs) and members of the LDL receptor family, particularly low-density lipoprotein receptor-related protein 1 (LRP1), which regulate the handling of proteopathic seeds like tau, α-synuclein, and amyloid-β. Phosphatidylserine readers and complement components were found to shape myeloid cell capture and inflammatory responses. Integrin, tetraspanin, and ICAM-1 nanoclusters influence EV avidity, organotropism, and immune suppression. At the BBB, endothelial HSPGs, LRP1, and transferrin receptor (TfR) support receptor-mediated uptake. > Engineered ligands, such as rabies virus glycoprotein-derived peptides, Angiopep-2, and TfR binders, show promise in enhancing BBB penetration. However, endosomal escape remains a major kinetic barrier for efficient nucleic acid delivery, highlighting a critical challenge for EV-based gene therapies.