Plasma-derived exosome-like vesicles are enriched in lyso-phospholipids and pass the blood-brain barrier

Abstract

Exosomes are vesicles involved in intercellular communication. Their membrane structure and core content is largely dependent on the cell of origin. Exosomes have been investigated both for their biological roles and their possible use as disease biomarkers and drug carriers. These potential technological applications require the rigorous characterization of exosomal blood brain barrier permeability and a description of their lipid bilayer composition. To achieve these goals, we have established a 3D static blood brain barrier system based on existing systems for liposomes and a complementary LC-MS/MS and 31 P nuclear magnetic resonance methodology for the analysis of purified human plasma-derived exosomelike vesicles. Results show that the isolated vesicles pass the blood brain barrier and are taken up in endothelial cells. The compositional analysis revealed that the isolated vesicles are enriched in lyso phospholipids and do not contain phosphatidylserine. These findings deviate significantly from the composition of exosomes originating from cell culture, and may reflect active removal by macrophages that respond to exposed phosphahtidylserine.

Factors Affecting Extracellular Vesicles Based Drug Delivery Systems

“…EVs derived from biofluids such as plasma [ 124 ], and ascites [ 125 ], have shown potential as delivery carriers. Biofluid-derived EVs have several advantages as delivery carriers.…”

“…For example, unlike cell culture-derived EVs, plasma-derived EVs are enriched with lyso-phospholipids and do not contain phosphatidylserine (PS). The absence of PS on the surface of plasma-derived EVs prevent their removal from circulation [ 124 , 126 ]. In addition, plasma-derived EVs can cross the blood-brain barrier (BBB), which suggests their applicability for brain delivery [ 124 ].…”

“…The absence of PS on the surface of plasma-derived EVs prevent their removal from circulation [ 124 , 126 ]. In addition, plasma-derived EVs can cross the blood-brain barrier (BBB), which suggests their applicability for brain delivery [ 124 ]. Ascites-derived EVs along with granulocyte–macrophage colony-stimulating factor have been found to be safe and effective for immunotherapy of colorectal cancer [ 125 ].…”

Extracellular Vesicles Taken up by Astrocytes

“…It has been shown that EVs in peripheral blood can pass through the blood–brain barrier (BBB) [ 34 , 35 ]. Furthermore, it has been reported that neuron-derived EVs are taken up by endothelial cells and that the expression of endothelial cadherin is increased by miR132 contained in EVs [ 24 ], suggesting that neuronal EVs may be involved in the regulation of BBB integrity.…”

Native and Bioengineered Exosomes for Ischemic Stroke Therapy

“…Interaction between exosomes and BMECs in vitro shows that, in healthy and stroke-like conditions, exosomes retain their BBB crossing ability ( Chen et al, 2016 ). Exosomes crossed the BBB and were taken up by endothelial cells in a 3-D BBB static model ( Jakubec et al, 2020 ). This finding of exosome BBB crossing has been confirmed by a number of studies ( Grapp et al, 2013 ; Long et al, 2017 ; Yuan et al, 2017 ; Qu et al, 2018 ) however, biodistribution studies of exosomes reveal that, after intravenous administration of native exosomes to the body, they were rapidly cleaned from the target site and accumulated in organs of the reticuloendothelial system, such as the lungs, liver, and spleen, and very few exosomes were found at the target site ( Lai et al, 2014 ; Wiklander et al, 2015 ; Tian et al, 2018 ; Lu and Huang, 2020 ).…”