{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:29:37Z","timestamp":1791944977408,"version":"4.3.4"},"reference-count":68,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"BBSRC","doi-asserted-by":"publisher","award":["BB\/V001418\/1"],"award-info":[{"award-number":["BB\/V001418\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK Multidisciplinary Award","doi-asserted-by":"publisher","award":["C57744\/A22057"],"award-info":[{"award-number":["C57744\/A22057"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"EPSRC","doi-asserted-by":"publisher","award":["EP\/W009889\/1"],"award-info":[{"award-number":["EP\/W009889\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"School of Pharmacy, The University of Nottingham, UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tau pathology is a defining hallmark of Alzheimer\u2019s disease (AD), closely associated with cognitive decline. Antisense oligonucleotides targeting the tau-encoding gene MAPT (MAPT-ASO) have shown promise in clinical trials, but their therapeutic potential is limited by poor delivery across the blood\u2013brain barrier (BBB). In this study, we developed transferrin (TF)-functionalized liposomes encapsulating MAPT-ASOs and evaluated their transport across a 3D self-assembled microvascular BBB model composed of human brain microvascular endothelial cells, astrocytes, and pericytes embedded in a fibrin hydrogel. Following confirmation of MAPT-ASO efficacy in reducing tau levels and protecting against glutamate-induced axonal degeneration, we observed significantly enhanced extravascular accumulation and sustained delivery of MAPT-ASOs with TF-functionalized liposomes over 24 h, compared to non-functionalized control liposomes. This study presents a novel delivery strategy for a functionally effective tau-targeting anti-sense oligonucleotide (ASO), potentially enabling systemic delivery rather than intrathecal administration. In addition, this study demonstrates the utility of the 3D in vitro BBB model for screening and optimizing brain delivery of nucleic acid-based therapeutics.<\/jats:p>","DOI":"10.3390\/ijms262311347","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T13:09:25Z","timestamp":1763989765000},"page":"11347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Transferrin-Functionalized Liposomes Enhance MAPT-ASO Transport Across a 3D Blood\u2013Brain Barrier Microvascular Network Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1052-0304","authenticated-orcid":false,"given":"Simon","family":"Konig","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2112-0510","authenticated-orcid":false,"given":"Xinai","family":"Shen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-0351","authenticated-orcid":false,"given":"Giuseppe","family":"Mantovani","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0476-162X","authenticated-orcid":false,"given":"Gerlof Sebastiaan","family":"Winkler","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-3812","authenticated-orcid":false,"given":"Zheying","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7019-3907","authenticated-orcid":false,"given":"Emad","family":"Moeendarbary","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, University College London, London WC1E 6BT, UK"},{"name":"BioRecode Ltd., London EC4N 7BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","unstructured":"Alzheimer\u2019s Association (2025). 2025 Alzheimer\u2019s disease facts and figures. 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