Extracellular vesicles through the blood–brain barrier

Extracellular vesicles (EVs) are particles naturally released from cells that are delimited by a lipid bilayer and are unable to replicate. How the EVs cross the Blood-Brain barrier (BBB) in a bidirectional manner between the bloodstream and brain parenchyma remains poorly understood. Most in vitro models that have evaluated this event have relied on monolayer transwell or microfluidic organ-on-a-chip techniques that do not account for the combined effect of all cellular layers that constitute the BBB at different sites of the Central Nervous System. There has not been direct transcytosis visualization through the BBB in mammals in vivo, and evidence comes from in vivo experiments in zebrafish. Literature is scarce on this topic, and techniques describing the mechanisms of EVs motion through the BBB are inconsistent. Researchers from the Pontifical Catholic University of Chile focus on in vitro and in vivo methodologies used to evaluate EVs transcytosis, how EVs overcome this fundamental structure, and discuss potential methodological approaches for future analyses to clarify these issues. Understanding how EVs cross the BBB will be essential for their future use as vehicles in pharmacology and therapeutics.

Uptake and transcytosis mechanisms for crossing of extracellular vesicles through the BBB

The figure shows four uptake mechanisms that have been evaluated and proposed for the active transport of EVs across the BBB and the authors that have described evidence to support them: A Macropinocytosis. B Clathrin-mediated endocytosis. C Caveolae-mediated endocytosis. D Adsorptive-mediated endocytosis. The fate of EVs after internalization include recycling to the plasma membrane, degradation of EVs by lysosomes, and final transcytosis of EVs and their cargos to the extracellular space. EVs extracellular vesicles, BBB blood brain barrier, MVB multivesicular body, TJ tight junctions