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Extracellular vesicles (EVs) are promising analytical targets because they carry molecular cargo from their originating cells, but tumor\u2010associated EV signals can be rare in blood and obscured in bulk measurements. Here, we present\n                    <jats:bold>Cygnus<\/jats:bold>\n                    (\n                    <jats:bold>Cy<\/jats:bold>\n                    clic\u2010imaging\n                    <jats:bold>g<\/jats:bold>\n                    ateway to\n                    <jats:bold>n<\/jats:bold>\n                    anovesicles\n                    <jats:bold>u<\/jats:bold>\n                    nderlying\n                    <jats:bold>s<\/jats:bold>\n                    ignature), an end\u2010to\u2010end workflow that integrates cyclic immunofluorescence imaging with multiscale analysis of individual EVs. Cygnus preserves vesicle\u2010level measurements, quantifies marker co\u2010expression, resolves EV subpopulations, and summarizes single\u2010vesicle phenotypes into sample\u2010level profiles. In a genetically engineered mouse model of lung adenocarcinoma, Cygnus revealed dynamic changes in EV protein composition and identified an EpCAM\u2010 and\/or CTSH\u2010positive EV subpopulation before tumors were detectable by radiography. In a pilot clinical cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a035), plasma EV profiling showed lung cancer\u2010associated marker patterns compared with non\u2010cancer controls and nominated a CTSH\/PDL1\/MET marker combination for future validation. These findings support multiplexed individual\u2010EV profiling as a strategy for defining candidate lung cancer\u2010associated EV signatures and position Cygnus as an integrated workflow for translating vesicle\u2010level heterogeneity into sample\u2010level EV profiles.\n                  <\/jats:p>","DOI":"10.1002\/advs.77301","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:20:04Z","timestamp":1787664004000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiplexed Profiling of Individual Extracellular Vesicles Reveals Lung Cancer\u2010Associated Protein Signatures"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9429-4692","authenticated-orcid":false,"given":"Mi Hyeon","family":"Cho","sequence":"first","affiliation":[{"name":"Center For Systems Biology Massachusetts General Hospital Research Institute  Boston Massachusetts USA"},{"name":"Department of Radiology, Harvard Medical School Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Metropolitan Seoul Center Korea Basic Science Institute (KBSI)  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yein","family":"Chung","sequence":"additional","affiliation":[{"name":"Center For Systems Biology Massachusetts General Hospital Research Institute  Boston Massachusetts USA"},{"name":"Department of Immunology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4422-604X","authenticated-orcid":false,"given":"Yoonjeong","family":"Choi","sequence":"additional","affiliation":[{"name":"Center For Systems Biology Massachusetts General Hospital Research Institute  Boston Massachusetts USA"},{"name":"Department of Radiology, Harvard Medical School Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baekdong","family":"Cha","sequence":"additional","affiliation":[{"name":"Department of Industrial Machinery DX. 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