Delivery of Mrna Vaccine with 1, 2-diesters-derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy.

messenger RNA (mRNA) vaccine has been explored as a promising strategy for cancer immunotherapy, but the side effects especially the liver-related damage caused by LNP raise concerns about its safety. In this study, we designed a novel library of 248 ionizable lipids comprising 1,2-diesters via a two-step process involving the epoxide ring-opening reaction with carboxyl group-containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2-diesters, our top-performing lipids and formulations exhibited a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin-MC3-DMA. Moreover, our LNP showed superior intramuscular mRNA delivery and elicited robust antigen-specific immune activation. The vaccinations delivered by our LNP system suppressed tumor growth and prolonged survival in both model human papillomavirus E7 and ovalbumin antigen-expressing tumor models. Finally, we further optimized the structure of lipids which enhanced the protein expression in the spleen and draining lymph nodes compared with ALC-0315 lipid in Comirnaty. In conclusion, the 1, 2-diester-derived lipids exhibited rapid liver clearance and effective anti-cancer efficiency to different types of antigens-expressing tumor models, which might be a safe and universal platform for mRNA vaccines. This article is protected by copyright. All rights reserved.