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EVs carry molecular cargo such as proteins, nucleic acids, and lipids that mirror those at the tissue of origin, offering unique opportunities to quantify disease-related changes in biomarkers. Compared with plasma-derived EVs, those from CSF provide more direct insights into the CNS because of direct shedding of brain EVs to CSF and bypass of confounding factors involving entry to systemic circulation. Despite this potential, translation into clinical practice is limited by challenges such as low yields, purity concerns, and lack of standardized isolation protocols. Addressing these difficulties, alongside integrating multiomics approaches, will advance our understanding of EV molecular cargo and their functional roles in CNS diseases. Over time, CSF-derived EVs could become the new driver of precision medicine in neurology, offering biologic insight for both diagnostic and therapeutic applications. This perspective provides a critical evaluation of the current status of EV-based liquid biopsy in CSF and offers recommendations for future research and clinical translation of data from CSF-derived EVs, highlighting their potential to inform physiologically based pharmacokinetic (PBPK) models. This state-of-the-art article evaluates existing evidence and highlights key knowledge gaps.<\/jats:p>","DOI":"10.1007\/s12035-026-06074-6","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:57:04Z","timestamp":1784811424000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The New Spine of Access to the Brain\u2019s Secrets: Extracellular Vesicles from Cerebrospinal Fluid Liquid Biopsies in CNS Diseases and Blood\u2013Brain Barrier Research"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8355-9704","authenticated-orcid":false,"given":"Isabeau","family":"Vermeulen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Parmentier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-0291","authenticated-orcid":false,"given":"Jill","family":"Barber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Fran\u00e7ois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5524-3139","authenticated-orcid":false,"given":"Loubna","family":"Chadli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3813-3892","authenticated-orcid":false,"given":"Nicolas","family":"Provost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3402-7685","authenticated-orcid":false,"given":"Emre M.","family":"Isin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2446-6895","authenticated-orcid":false,"given":"Kayode","family":"Ogungbenro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3933-5217","authenticated-orcid":false,"given":"Aleksandra","family":"Galetin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami-Hodjegan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-3140","authenticated-orcid":false,"given":"Zubida M.","family":"Al-Majdoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"issue":"5","key":"6074_CR1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.2471\/blt.17.206599","volume":"96","author":"M Di Luca","year":"2018","unstructured":"Di Luca M, Nutt D, Oertel W, Boyer P, Jaarsma J, Destrebecq F, Esposito G, Quoidbach V (2018) Towards earlier diagnosis and treatment of disorders of the brain. 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