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Short interfering RNAs (siRNAs), in particular, are gaining\u00a0interest for treating\u00a0neurological diseases owing to their capacity to sustain inhibition of nearly any gene target. However, to be effective, siRNA therapies must achieve delivery and on-target gene silencing activity in specific sites and cells in the brain. To this end, we developed a lipid\u2013siRNA conjugate (L2-siRNA) that transports effectively throughout the brain when injected into cerebrospinal fluid (CSF). We provide a detailed examination of regional bulk tissue gene silencing in mice, highlighting potent knockdown 5 months after a single injection without detectable toxicity. Intrathecal delivery of L2-siRNA in rats further illustrates effective transport and knockdown using a clinically relevant route of administration. Single-cell RNA sequencing was additionally performed in mice to generate an atlas of cell type-specific knockdown. Lastly, we benchmarked L2-siRNA gene silencing activity in different brain regions against antisense oligonucleotides, a related but different gene silencing modality. Collectively, this work examines properties of lipid\u2013siRNA conjugates that facilitate CSF\u00a0to brain delivery and supports L2-siRNA as a promising platform for silencing genes implicated in central nervous system\u00a0disorders.<\/jats:p>","DOI":"10.1093\/nar\/gkaf600","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T05:34:45Z","timestamp":1751434485000},"source":"Crossref","is-referenced-by-count":11,"title":["Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid\u2013siRNA conjugate administered into cerebrospinal fluid"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9406-5611","authenticated-orcid":false,"given":"Alexander\u00a0G","family":"Sorets","sequence":"first","affiliation":[{"name":"Vanderbilt University Department of Biomedical Engineering, , Nashville , TN 37240 ,","place":["United 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