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After regression of the notochord, notochordal cells (NCs) reside within the developing intervertebral disc. The NC\u2010secretome, including matrix, proteins and extracellular vesicles (NC\u2010EVs), promotes regeneration of degenerate intervertebral discs and cartilage. This study aims to unravel the NC\u2010EV\u2010associated proteome and modulatory role in regenerative processes. NC\u2010EVs were isolated from conditioned medium from porcine NC\u2010rich tissue using differential centrifugation, size exclusion chromatography and density gradient centrifugation. Proteomic analysis of NC\u2010EVs was performed using LC\u2010MS\/MS and identified 4042 unique proteins, including EV\u2010associated markers, matrisome proteins and proteins associated with critical nodes in canonical signalling pathways. To test NC\u2010EV bioactivity, functional analysis was performed using SBE, TCF\/LEF and NF\u2010\u03baB luciferase reporters. NC\u2010EVs activated SMAD3 and inhibited IL\u20101\u03b2\u2010mediated NF\u2010\u03baB signalling. NC\u2010EV depleted controls showed similar effects, indicating that co\u2010isolated proteins played a major role in modulating signalling. Therefore, NC\u2010EVs were further purified and the GAG\u2010rich biomolecular corona was modified with hyaluronidase. Post\u2010hyaluronidase treatment, SMAD3 activation was enhanced only in methodological controls, while inhibition of IL\u20101\u03b2\u2010mediated NF\u2010\u03baB signalling was NC\u2010EV specific. This study is the first to reveal the NC\u2010EV proteome and illustrates that proteins absorbed on the NC\u2010EVs attribute to EV\u2010mediated functional effects.<\/jats:p>","DOI":"10.1002\/jex2.70186","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:52:22Z","timestamp":1789368742000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteomic Atlas of Notochordal Cell\u2010Derived Extracellular Vesicles Highlights EV\u2010Specific NF\u2010\u03baB Modulation and Functional Implications of the Protein Corona"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0709-4735","authenticated-orcid":false,"given":"Josette C.","family":"van Maanen","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8113-2682","authenticated-orcid":false,"given":"Chantal","family":"Voskamp","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4732-9447","authenticated-orcid":false,"given":"Frank M.","family":"Riemers","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4696-6068","authenticated-orcid":false,"given":"Harmjan R.","family":"Vos","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine University Medical Center Utrecht  Utrecht the Netherlands"},{"name":"Utrecht University, Oncode Institute  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1416-5853","authenticated-orcid":false,"given":"Anouk","family":"Eversdijk","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4728-1142","authenticated-orcid":false,"given":"Marije","family":"Kleinjan","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Health Sciences Faculty of Veterinary Medicine Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1069-6640","authenticated-orcid":false,"given":"Menno","family":"Bergmeijer","sequence":"additional","affiliation":[{"name":"Structural Biochemistry, Bijvoet Center for Biomolecular Research Utrecht University  Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn J. 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