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However, effective mRNA delivery to the central nervous system (CNS) remains a formidable challenge. To overcome this limitation, a class of brain\u2010targeting lipids (BLs) is developed by incorporating brain\u2010targeting small molecules with amino lipids and formulated them with helper lipids to generate brain\u2010targeting lipid nanoparticles (BLNPs) for mRNA delivery. Screening studies led to a lead formulation, TD5 BLNPs, outperforming FDA\u2010approved DLin\u2010MC3\u2010DMA LNPs in delivering mRNA to the brain upon intrathecal injection. Specifically, a single intrathecal injection of TD5 BLNP\u2010GFP mRNA led to GFP expression in 29.6% of neurons and 38.1% of astrocytes across the brain. In an Ai14 mouse model, TD5 BLNP\u2010Cre recombinase mRNA treatment induced tdTomato expression in \u224830% of neurons and 40% of astrocytes across major brain regions. Notably, delivery of Cas9 mRNA\/sgRNA complex using TD5 BLNPs achieved effective genome editing in the brain. Additionally, TD5 BLNPs showed comparable safety profiles to MC3 LNPs, indicating promising biocompatibility. Overall, this TD5 BLNP formulation effectively delivers mRNA to brain tissues via intrathecal injection and facilitates efficient expression in both neurons and astrocytes, presenting a potential strategy for treating CNS diseases.<\/jats:p>","DOI":"10.1002\/adma.202417097","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T11:32:32Z","timestamp":1746271952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection"],"prefix":"10.1002","volume":"37","author":[{"given":"Yonger","family":"Xue","sequence":"first","affiliation":[{"name":"Icahn Genomics Institute Precision Immunology Institute Department of Immunology and Immunotherapy Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"},{"name":"Division of Pharmaceutics &amp; Pharmacology College of Pharmacy The Ohio State 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