Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undoubtedly the most challenging pandemic in the current century and remains a global health emergency. As the number of COVID-19 cases in the world is on the rise and variants continue to emerge, there is an urgent need for vaccines. Among all immunization approaches, mRNA vaccines have demonstrated more promising results in response to this challenge. Herein, we designed an mRNA-based vaccine encoding the receptor-binding domain (RBD) of SARS-CoV-2 encapsulated in lipid nanoparticles (LNPs). Intramuscular (i.m.) administration of the mRNA-RBD vaccine elicited broad-spectrum neutralizing antibodies and cellular responses against not only the wild-type SARS-CoV-2 virus but also Delta and Omicron variants. These results indicated that two doses of mRNA-RBD immunization conferred a strong immune response in mice against the wild-type SARS-CoV-2, while the booster dose provided a sufficient immunity against SARS-CoV-2 and its variants. Taken together, the three-dose regimen strategy of the mRNA-RBD vaccine proposed in the present study appears to be a promising reference for the development of mRNA vaccines targeting SARS-CoV-2 variants.

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.