Messenger RNA (mRNA) therapeutics have shown considerable promise across a wide range of medical applications with lipid nanoparticles (LNPs) emerging as the most clinically advanced mRNA delivery vehicles. However, the risk of off-target tissue delivery remains a concern, underscoring the need for diverse ionizable lipids to optimize LNP-based delivery systems. In this study, we designed and synthesized a library of 21 novel ionizable lipids and evaluated their potential for mRNA delivery. The resulting LNPs displayed favorable physicochemical properties and low cytotoxicity. In vitro transfection assay identified 3 high efficiency LNPs: YK-305, YK-310 and YK-319. In a mouse model, intramuscular injection of firefly luciferase (Fluc) mRNA-LNPs resulted in high transfection efficiency in muscle tissue, with significantly reduced gene expression in the liver. After encapsulating varicella zoster virus (VZV) glycoprotein E (gE)-encoding mRNA, the three LNP formulations induced robust humoral and cellular immune responses specific to the gE antigen, demonstrated improved selectivity and immunogenicity compared to SM-102, the ionizable lipid used in Moderna’s Spikevax. The safety of the gE-mRNA LNP formulations were subsequently demonstrated in a mouse model. Collectively, these findings provide a foundation for the optimization of tissue-targeting ionizable lipids and highlight their potential to advance mRNA-based vaccines in clinical applications. Graphical abstract
Gege Zeng,Zepeng He,Haihong Yang,Zhan Gao,Xueer Ge,Lixin Liu,Zhijia Liu,Yongming Chen
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.
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