Engineering extracellular vesicles to transiently permeabilize the blood-brain barrier.

Background: Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain.
Results: Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4).
Conclusions: Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream.
Competing Interests: Declarations. Ethics approval and consent to participate: The collection of umbilical cord blood (UCB) was approved by the ethical committee of Dr. Daniel de Matos Maternity Hospital in Coimbra (protocol HUC-01-11), Portugal. The collection of adult blood was approved by the Faculty of Medicine of the University of Coimbra and the Portuguese Institute for Blood and Transplantation (IPST) in the facilities of Blood and Transplantation Center of Coimbra (CSTC) (protocol: CE-088/2020). All the donors of the UCB and adult blood signed an informed consent form, in compliance with the Portuguese legislation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)