{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:44:10Z","timestamp":1775979850112,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,17]]},"group-title":"Bioengineering","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Barriers of the central nervous system (CNS), such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), regulate the two-way exchange of material between the blood and CNS. These barriers pose a considerable challenge for efficacious delivery of intravenously administered therapies into the CNS, motivating exploration of their function and ways to modulate their properties. While the BBB and BCSFB can become dysfunctional in patients with chronic CNS diseases, few studies have focused on strategies for targeting these interfaces. Here, we showed that an intravenously administered albumin-binding lipid-siRNA conjugate was delivered to and silences genes within brain endothelial cells and choroid plexus epithelial cells, which comprise the BBB and BCSFB, respectively. A single intravenous dose of lipid-siRNA conjugate was delivered to \u223c100% of brain endothelial cells and major choroid plexus cell types, without any substantial delivery into brain parenchymal tissue. Sustained gene silencing was achieved in both brain endothelial cells (over two weeks) and bulk choroid plexus tissues (up to one month). Moreover, single cell RNA sequencing demonstrated gene knockdown in capillaries, venous endothelial cells, and choroid plexus epithelial cells without silencing genes in parenchymal cell populations. Collectively, this work establishes an effective nonviral framework to mediate gene inhibition in the brain barriers.<\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHICAL ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"642142v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.14.642142","type":"posted-content","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T15:51:41Z","timestamp":1742399501000},"source":"Crossref","is-referenced-by-count":0,"title":["Intravenous lipid-siRNA conjugate mediates gene silencing at the blood-brain barrier and blood-CSF barrier"],"prefix":"10.64898","author":[{"given":"Alexander G.","family":"Sorets","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrina R.","family":"Schwensen","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora","family":"Francini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Kjar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Lyons","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular 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