@article{f8585d68cf9646d0b1ebffebcc1b8eed,
title = "A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo",
abstract = "Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol-based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3-Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3-Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18-fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.",
keywords = "lipid nanoparticles, mRNA, nanomaterials, unsaturated lipids, unsaturated thiols",
author = "Lee, {Sang M.} and Qiang Cheng and Xueliang Yu and Shuai Liu and Johnson, {Lindsay T.} and Siegwart, {Daniel J.}",
note = "Funding Information: D.J.S. acknowledges financial support from the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 EB025192‐01A1), the Cystic Fibrosis Foundation (CFF) (SIEGWA18XX0), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP190251), the American Cancer Society (ACS) (RSG‐17‐012‐01), and the Welch Foundation (I‐1855). We acknowledge the UTSW Small Animal Imaging Shared Resource (NIH NCI P30CA142543). S.M.L. acknowledges support from NIH (T32GM127216). Funding Information: D.J.S. acknowledges financial support from the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 EB025192-01A1), the Cystic Fibrosis Foundation (CFF) (SIEGWA18XX0), the Cancer Prevention and Research Institute of Texas (CPRIT) (RP190251), the American Cancer Society (ACS) (RSG-17-012-01), and the Welch Foundation (I-1855). We acknowledge the UTSW Small Animal Imaging Shared Resource (NIH NCI P30CA142543). S.M.L. acknowledges support from NIH (T32GM127216). Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2021",
month = mar,
day = "8",
doi = "10.1002/anie.202013927",
language = "English (US)",
volume = "60",
pages = "5848--5853",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "11",
}