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Small extracellular vesicles (sEVs) have emerged as promising biomarkers for early cancer detection and disease monitoring due to their omnipresence and stability in bodily fluids, such as blood plasma. In addition, cancer-derived sEVs specifically carry cargo reflective of oncogene-derived molecular alterations. In summary, these characteristics position sEVs as a potential platform for non-invasive testing of HNSCC. Methods: Plasma-derived sEVs from HNSCC patients (n = 71) and benign subjects (n = 25) were isolated using size exclusion chromatography. Proteomic profiling via liquid chromatography-tandem mass spectrometry identified potential candidate biomarkers, followed by ELISA validation. Results: Proteomic analyses revealed a significant enrichment of multiple proteins in HNSCC-derived sEVs compared to sEVs derived from non-cancer individuals. The von Willebrand factor (vWF) was significantly higher in HNSCC patient-derived sEVs compared to those derived from benign individuals. A validation cohort confirmed that sEV-associated vWF (sEV-vWF) effectively distinguished HNSCC patients from benign subjects, demonstrating strong diagnostic performance, specifically in laryngeal HNSCC (AUC = 0.82) and oropharyngeal HNSCC (AUC = 0.96) patient cohorts. Moreover, postoperative reductions and recurrence-associated increases in sEV-vWF levels corresponded with clinical outcomes, indicating its potential as a dynamic disease indicator. Conclusions: These findings highlight sEV-vWF as a novel and non-invasive biomarker with potential applications in early detection and real-time monitoring of HNSCC, supporting advancement toward precision liquid biopsy strategies in head and neck oncology.<\/jats:p>","DOI":"10.3390\/cancers18142339","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"2339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of von Willebrand Factor-Enriched Small Extracellular Vesicles as a Blood-Based Biomarker for the Detection of Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6398-1571","authenticated-orcid":false,"given":"Yue","family":"Su","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"JC STEM Lab of Personalised Cancer Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8393-4209","authenticated-orcid":false,"given":"Kekoolani S.","family":"Visan","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"JC STEM Lab of Personalised Cancer Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunyoung","family":"Ham","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"JC STEM Lab of Personalised Cancer Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"JC STEM Lab of Personalised Cancer Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"},{"name":"JC STEM Lab of Personalised Cancer Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cherrie W. K.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-121X","authenticated-orcid":false,"given":"Judy Wai Ping","family":"Yam","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"},{"name":"State Key Laboratory of Liver Research (The University of Hong Kong), Hong Kong SAR, China"},{"name":"Materials Innovation Institute for Life Sciences and Energy (MILES), The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen 518045, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-4637","authenticated-orcid":false,"given":"Jason Y. 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