Extracellular vesicles through the blood-brain barrier: a review

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. This review will 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.

Automated summary

Extracellular vesicles (EVs) are non-replicative particles released from cells. The mechanism of bidirectional EVs transport across the blood-brain barrier (BBB) is poorly understood. Current research lacks direct visualization of EVs transcytosis through the BBB in mammals, with most studies relying on in vitro models that do not consider the combined effect of all cellular layers constituting the BBB. Further research using in vitro and in vivo methodologies is needed to clarify these issues.