Negative Surface Charge and Membrane Lipid Composition Underlying Extracellular Vesicle Function

Exosomes (EXOs), originating from multivesicular late endosomes and plasma-membrane-derived extracellular vesicles (PM-EVs), termed microvesicles, ectosomes, oncosomes, and apoptotic bodies, adopt a spherical shape with a lipid bilayer membrane and are released from various cells. EXOs play key roles in intercellular communication and physiological regulation. PM-EVs reflect cellular activation states and are involved in coagulation and inflammation. Both types of EVs possess an anionic surface charge resulting from scramblase-mediated translocation or nonenzymatic scrambling of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer, as observed in the membranes of dead cells. In addition, glycosphingolipids (GSLs) and glycoproteins containing sialic acid and phosphatidylinositol and its phosphorylated derivatives contribute to the negative charge on the EV surface. Anion-exchange column chromatography has shown that the surface of EXOs exhibits a weaker negative charge than that of other PM-EVs from the plasma membrane, correlating with the magnitude of the negative ζ-potential value. Furthermore, fluctuations in the ζ-potential values of EVs can be used to predict the biological and physiological states of the source cells. The PS proportion in the total membrane lipids of EVs is nearly equivalent between EXOs and other PM-EVs, suggesting that EXOs maintain membrane lipid asymmetry to some extent, similar to the plasma membrane of living cells, although the underlying mechanism remains unknown.