Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines. Ionizable cationic lipids are the most important component in LNPs. Herein, we developed a series of new ionizable lipids featuring bioreducible disulfide bonds, and constructed a library of lipids derived from dimercaprol. LNPs prepared from these ionizable lipids could be stored at 4 °C for a long term and are non-toxic toward HepG2 and 293T cells. In vivo experiments demonstrated that the best C4S18A formulations, which embody linoleoyl tails, show strong firefly luciferase (Fluc) mRNA expression in the liver and spleen via intravenous (IV) injection, or at the local injection site via intramuscular injection (IM). The newly designed ionizable lipids can be potentially safe and high-efficiency nanomaterials for mRNA therapy.
