biostudies-literatureMatsumoto AJapan Agency for Medical Research and DevelopmentMochida Memorial Foundation for Medical and Pharmaceutical ResearchUehara Memorial FoundationJapan Society for the Promotion of Science102839https://www.ebi.ac.uk/biostudies/studies/S-EPMC8326202biostudies-literatureUnknown24(8)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.iSciencePhosphatidylserine-deficient small extracellular vesicle is a major somatic cell-derived sEV subpopulation in blood.PMC8326202JP20H04533JP17K19390JP18H0256219ak0101120h000120ak0101120h000217fk0210104h0001Nakagawa NMatsumoto AKitamura SIshihama YTakakura YOgata KTakahashi YYamamoto AfalsePhosphatidylserine-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.2021-01-01T00:00:00Z2021 Aug2024-11-21T07:36:18.566Z2022-02-11T05:25:51.924ZS-EPMC83262023436865510.1016/j.isci.2021.102839