Delivery of mRNA Vaccine with 1, 2‐Diesters‐Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy

Abstract Messenger RNA (mRNA) vaccine is 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, a novel library of 248 ionizable lipids comprising 1,2‐diesters is designed 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, the top‐performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin‐MC3‐DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen‐specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen‐expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC‐0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2‐diester‐derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens‐expressing tumor models, which may be a safe and universal platform for mRNA vaccines.