{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:27:39Z","timestamp":1785432459060,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"the Ministry of Healthcare of the Russian Federation","doi-asserted-by":"publisher","award":["12503063216-9"],"award-info":[{"award-number":["12503063216-9"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"publisher"}]},{"award":["12503063216-9"],"award-info":[{"award-number":["12503063216-9"]}],"id":[{"id":"https:\/\/ror.org\/01p8ehb87","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Human papillomavirus (HPV)-associated cervical lesions remain a significant disease burden and minimally invasive blood-based biomarkers could complement cytology and HPV testing. This study aimed to characterize the proteomic composition of plasma-derived CD9+ small extracellular vesicles (sEVs) across the morphological spectrum of HPV-associated cervical disease, from histologically normal (NILM) through low-grade (LSIL) and high-grade (HSIL) lesions to invasive squamous cell carcinoma (SCC). Plasma samples from 34 women (NILM, LSIL, HSIL, SCC) were pooled per group, and CD9+ sEVs were isolated using an electrochemically controlled immunoaffinity capture method, followed by nanoparticle tracking analysis, transmission electron microscopy, Western blotting, and label-free LC\u2013MS\/MS proteomic profiling. The core sEV proteome comprised 258 shared proteins. LSIL showed the most pronounced changes with broad enrichment of complement and coagulation components and acute-phase reactants alongside depletion of immunoglobulin chains and complement C1r-like protein (C1RL). HSIL exhibited few differential proteins, dominated by neutrophil degranulation and retinoid metabolism pathways. SCC demonstrated extensive cargo depletion (22 downregulated proteins) and a nearly sevenfold upregulation of C1RL. Five proteins (including immunoglobulin chains and GPLD1) correlated positively with lesion severity. Pathway analysis consistently implicated platelet activation, lipoprotein remodeling, and insulin-like growth factor signaling. We conclude that plasma CD9+ sEVs carry stage-specific proteomic signatures distinguishing HPV-associated cervical lesions, with C1RL emerging as a candidate biphasic marker warranting further validation.<\/jats:p>","DOI":"10.3390\/life16071181","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:55:59Z","timestamp":1784249759000},"page":"1181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteome of CD9+ Plasma Small Extracellular Vesicles Differentiates Stages of HPV-Associated Cervical Neoplasia from Normal Epithelium to Invasive Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Alexander M.","family":"Yurin","sequence":"first","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-5915","authenticated-orcid":false,"given":"Natalia L.","family":"Starodubtseva","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"},{"name":"Moscow Center for Advanced Studies, 123592 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1515-9447","authenticated-orcid":false,"given":"Anna E.","family":"Bugrova","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"},{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2238-3458","authenticated-orcid":false,"given":"Alexey S.","family":"Kononikhin","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"},{"name":"The Center for Bio- and Medical Technologies, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0581-9755","authenticated-orcid":false,"given":"Denis N.","family":"Silachev","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"},{"name":"A.N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir E.","family":"Frankevich","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa O.","family":"Tokareva","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8177-7449","authenticated-orcid":false,"given":"Maria I.","family":"Indeykina","sequence":"additional","affiliation":[{"name":"Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia"},{"name":"The Center for Bio- and Medical Technologies, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-6818","authenticated-orcid":false,"given":"Ekaterina A.","family":"Evtushenko","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2546-5130","authenticated-orcid":false,"given":"Alexander A.","family":"Yakovlev","sequence":"additional","affiliation":[{"name":"Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A.","family":"Mezhevitinova","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene N.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"The Center for Bio- and Medical Technologies, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niso M.","family":"Nazarova","sequence":"additional","affiliation":[{"name":"V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera N.","family":"Prilepskaya","sequence":"additional","affiliation":[{"name":"V.I. 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