1. Cationic Lipid Pairs Enhance Liver-to-Lung Tropism of Lipid Nanoparticles for In Vivo mRNA Delivery.
- Author
-
Zeng G, He Z, Yang H, Gao Z, Ge X, Liu L, Liu Z, and Chen Y
- Subjects
- Animals, Humans, Mice, Gene Transfer Techniques, Transfection methods, Liposomes, Nanoparticles chemistry, Lung metabolism, RNA, Messenger metabolism, RNA, Messenger genetics, Lipids chemistry, Liver metabolism, Cations chemistry
- Abstract
Much of current clinical interest has focused on mRNA therapeutics for the treatment of lung-associated diseases, such as infections, genetic disorders, and cancers. However, the safe and efficient delivery of mRNA therapeutics to the lungs, especially to different pulmonary cell types, is still a formidable challenge. In this paper, we proposed a cationic lipid pair (CLP) strategy, which utilized the liver-targeted ionizable lipid and its derived quaternary ammonium lipid as the CLP to improve liver-to-lung tropism of four-component lipid nanoparticles (LNPs) for in vivo mRNA delivery. Interestingly, the structure-activity investigation identified that using liver-targeted ionizable lipids with higher mRNA delivery performance and their derived lipid counterparts is the optimal CLP design for improving lung-targeted mRNA delivery. The CLP strategy was also verified to be universal and suitable for clinically available ionizable lipids such as SM-102 and ALC-0315 to develop lung-targeted LNP delivery systems. Moreover, we demonstrated that CLP-based LNPs were safe and exhibited potent mRNA transfection in pulmonary endothelial and epithelial cells. As a result, we provided a powerful CLP strategy for shifting the mRNA delivery preference of LNPs from the liver to the lungs, exhibiting great potential for broadening the application scenario of mRNA-based therapy.
- Published
- 2024
- Full Text
- View/download PDF