Multi-omics reveal key protein and lipid features of small extracellular vesicles in human plasma

Extracellular vesicles are tiny packets released by cells that carry proteins, lipids and genetic material through the bloodstream. They help cells communicate and can provide important clues about health and disease. However, scientists still lack a clear picture of what these vesicles are made of at their core. To address this, researchers at the Baker Heart and Diabetes Institute, Australia analyzed more than 140 human plasma samples to create one of the most detailed maps of EV composition to date.

The team used high resolution fractionation and mass spectrometry to identify more than 4,500 proteins and 829 lipids contained within circulating EVs. From this massive dataset, they uncovered a highly conserved group of proteins and lipids that consistently appear in these vesicles. These include proteins such as ADAM10 and lipids such as PS and PIPs, which may serve as reliable markers for identifying genuine EVs. They also examined the outer surface of vesicles and found 151 proteins that help define EV diversity.

Hallmark molecular features of circulating EVs

Fig. 6

a, Resolving the protein and lipid componentry intrinsic to circulating EVs. These features are also conserved in EVs released by cultured cells. We submit EV features, namely ADAM10 and phosphatidyl serine PS(36:1), as biological markers for confident EV identification and potentially purity assessment. b, The open-source Shiny web tool will facilitate interrogation of protein and lipid features in pEVs and NonEVs and serve as a valuable repository to the research community for a clearer understanding of circulating EV biology. Boxplot show the median (centre line), 25th–-75th percentiles (box) and minima and maxima within 1.5× interquartile range (whiskers); individual data points are overlaid.

Importantly, the researchers also cataloged features that distinguish EVs from non EV particles found in plasma. This makes it easier for scientists to avoid contamination and focus on vesicles that truly matter for diagnostics and biological research. Their work even points to two strong EV markers, ADAM10 and PS(36:1), that can sharply separate EVs from other particle types.

This large scale effort offers a valuable resource for anyone studying extracellular vesicles or exosomes and the authors have made an interactive online tool available so researchers can explore the data. By improving the understanding of what EVs contain, the findings will help advance research into disease detection, biomarker discovery and cell to cell communication.

Availability – These findings can be explored via an open-source Shiny web tool (evmap.shinyapps.io/evmap/)

Rai A, Huynh K, Cross J, Poh Q H, Fang H, Claridge B, Duong T, Duarte C, Shaw J E, Marwick T H, Meikle P, Greening D W. (2025) Multi omics identify hallmark protein and lipid features of small extracellular vesicles circulating in human plasma Nat Cell Biol [Epub ahead of print]. [article]

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