Lipid bilayer fluidity and degree of order regulates small EVs adsorption on model cell membrane

TL;DR

This study investigates how the physical properties of cell membranes, specifically fluidity and order, influence the adsorption and fusion of small extracellular vesicles, revealing that membrane fluidity significantly affects sEVs uptake.

Contribution

It demonstrates the role of membrane fluidity and lipid domain organization in regulating sEVs interaction and fusion with model membranes, using atomic force microscopy.

Findings

sEVs preferentially interact with less fluid membrane regions

High cholesterol levels can disrupt ordered membrane domains

Membrane fluidity is a key factor in sEVs uptake regulation

Abstract

Small extracellular vesicles (sEVs) are known to play an important role in the communication between distant cells and to deliver biological information throughout the body. To date, many studies have focused on the role of sEVs characteristics such as cell origin, surface composition, and molecular cargo on the resulting uptake by the recipient cell. Yet, a full understanding of the sEV fusion process with recipient cells and in particular the role of cell membrane physical properties on the uptake are still lacking. Here we explore this problem using sEVs from a cellular model of triple-negative breast cancer fusing to a range of synthetic planar lipid bilayers both with and without cholesterol, and designed to mimic the formation of raft-like nanodomains in cell membranes. Using time-resolved Atomic Force Microscopy we were able to track the sEVs interaction with the different model membranes, showing the process to be strongly dependent on the local membrane fluidity. The strongest interaction and fusion is observed over the less fluid regions, with sEVs even able to disrupt ordered domains at sufficiently high cholesterol concentration. Our findings suggest the biophysical characteristics of recipient cell membranes to be crucial for sEVs uptake regulation.