Trehalose-based lipid improves mRNA vaccine safety

Abstract The rapid development of lipid nanoparticle (LNP)-formulated mRNA vaccines strongly contributed to overcoming the COVID-19 pandemic. However, in parallel with this success, the toxicity of ionizable cationic lipids has emerged as a potential issue in clinical safety because it might cause mRNA vaccine side effects, including myocarditis, anaphylaxis, and pericarditis. In this study, to reduce the risk posed by ionizable cationic lipids, we employed LNPs containing trehalose-based lipid (LNP-126), which increased the stability of the LNP-mRNA molecules. Trehalose has been shown to improve heart function and increase mRNA stability through hydrogen bond interactions. The LNP-126 was formulated with 50% fewer ionizable cationic lipids than a commercial LNP (LNP-128). Furthermore, the mRNA encoding the reporter gene was encapsulated by LNP-126 so that gene expression (Renilla luciferase) and organ toxicity could be examined. We also assessed immune efficiency immunizing mice that had been treated with an LNP-126-formulated mRNA vaccine expressing influenza hemagglutinin (HA). The results showed that LNP-126 reduced organ toxicity in the liver and heart compared to LNP-128, while maintaining gene expression and immune efficiency in vivo. In conclusion, the LNP-126, trehalose-based lipid will facilitate the development of safer mRNA vaccines beyond the current barriers. A grant (22213MFDS421) from the Ministry of Food and Drug Safety in 2022 supported this research