Premium
A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo
Author(s) -
Lee Sang M.,
Cheng Qiang,
Yu Xueliang,
Liu Shuai,
Johnson Lindsay T.,
Siegwart Daniel J.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202013927
Subject(s) - degree of unsaturation , in vivo , endosome , chemistry , messenger rna , transfection , in vitro , microbiology and biotechnology , biochemistry , biophysics , biology , cell , gene , organic chemistry
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.