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In this study, we fractionate blood plasma by combining size\u2010exclusion chromatography (SEC) and OptiPrep density gradient centrifugation to study clinical context\u2010dependent and time\u2010dependent variations in the biomolecular landscape of systemically circulating EV. Using pooled blood plasma samples from breast cancer patients, we first demonstrate the technical repeatability of blood plasma fractionation. Using serial blood plasma samples from HIV and ovarian cancer patients (n\u00a0=\u00a010) we next show that EV carry a clinical context\u2010dependent and\/or time\u2010dependent protein and small RNA composition, including miRNA and tRNA. In addition, differential analysis of blood plasma fractions provides a catalogue of putative proteins not associated with systemically circulating EV. In conclusion, the implementation of blood plasma fractionation allows to advance the biological understanding and biomarker development of systemically circulating EV.<\/jats:p>","DOI":"10.1002\/jev2.12122","type":"journal-article","created":{"date-parts":[[2021,8,14]],"date-time":"2021-08-14T04:58:46Z","timestamp":1628917126000},"source":"Crossref","is-referenced-by-count":75,"title":["Robust sequential biophysical fractionation of blood plasma to study variations in the biomolecular landscape of systemically circulating extracellular vesicles across clinical conditions"],"prefix":"10.1002","volume":"10","author":[{"given":"Glenn","family":"Vergauwen","sequence":"first","affiliation":[{"name":"Department of Human Structure and Repair Laboratory of Experimental Cancer Research Ghent University  Ghent Belgium"},{"name":"Cancer Research Institute Ghent  Ghent Belgium"},{"name":"Department of Gynecology Ghent University Hospital  Ghent 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