Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy

Messenger ribonucleic acid (mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles (LNPs) are the most extensively applied non-viral platform for RNA delivery in clinics. Despite the clinical success of LNPs as vehicles have been achieved, developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and challenging. In this study, we designed a series of new ionizable amino lipids with piperazine-derived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA cargos. Among them, LNP formulated with lipid 10 (L10-LNP) can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo , which is mainly attributed to the improved intracellular uptake and effective endosomal escape. We verified that a single administration of L10-LNP packaging interleukin (IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8 + T cells and stimulating the generation of IFN-γ without causing systemic toxicity, which provides a promising platform for clinical cancer immunotherapy.