Development of a Library of Disulfide Bond-Containing Cationic Lipids for mRNA Delivery

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 degrees 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.

Automated summary

Researchers developed a series of ionizable lipids with bioreducible disulfide bonds and constructed a lipid library derived from dimercaprol. Lipid nanoparticles (LNPs) prepared from these ionizable lipids can be stored at 4 degrees C for a long term and are non-toxic to HepG2 and 293T cells. In vivo experiments showed that the best C4S18A formulations demonstrated 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). These newly designed ionizable lipids could be potentially safe and high-efficiency nanomaterials for mRNA therapy.