Phosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood

Small extracellular vesicles (sEVs) are important mediators of intercellular communication with respect to diverse pathophysiological processes. Here, we determined novel phosphatidylserine (PS)-deficient sEV subpopulations as a major somatic cell-derived sEV subpopulation in blood because of long blood circulation half-life through escape from macrophage uptake. PS^(-)-sEVs were identified in various cultured cells as a minor population. However, as a result of rapid uptake of PS⁽⁺⁾-sEVs by macrophages, circulating somatic cell-derived sEVs in the blood were found to be mainly PS^(-)-sEVs. These results suggest that endogenous PS^(-)-sEVs could indeed be the key player in sEV-mediated intercellular communication, a good target for sEV-based diagnosis, and a potent candidate for sEV-based drug delivery. Our findings bring a paradigm shift in the understanding of the biology and translational applications of sEVs.