Cost-effective yet high-performance ionizable lipids for mRNA-lipid nanoparticle vaccines

Ionizable lipids (ILs) are critical components in mRNA vaccines, which have been instrumental in the global response to SARS-CoV-2. However, current commercialized ILs in mRNA vaccines are typically synthesized through multiple-step organic reactions, complicating quality control and driving up production costs. To address this, we have developed novel ILs by a one-pot Ugi four-component reaction (Ugi-4CR), significantly simplifying synthesis while maintaining high yields and reducing costs. Here, from a library of 161 ILs, we chose six ILs with high expressing luciferase and investigated their performance in delivering the mRNA vaccine of SARS-CoV-2. These ILs feature distinct ionizable heads, N,N-dimethylethyl (R1), N,N-dimethylpropyl (R2), and N,N-diethylpropyl (R3), paired with hydrophobic tails of varying unsaturation, cis-9-octadecenoic (U1) and (9Z,12Z)-9,12-octadecadienoic (U2), respectively. In murine…