Engineered lipid nanoparticles with synergistic dendritic cell targeting and enhanced endosomal escape for boosted mRNA cancer vaccines.

Lipid nanoparticles (LNPs) have emerged as a pivotal carriers for enhancing mRNA therapeutics, particularly in antitumor therapy. However, achieving robust antigen expression remains a major challenge due to limitations in precise targeted delivery and inefficient endosomal escape. In this study, we constructed an ambidextrous LNP to achieve robust tumor-specific antigen expression through targeted cell delivery and enhanced endosomal escape of mRNA-LNPs. To improve endosomal escape, we synthesized a novel pH-responsive PEGylated lipid designed to synergistically enhance membrane fusion effect with ionizable lipids, thereby optimizing the translation of the desired antigen. This is accomplished by promoting the early endosomal escape and endosomal recycling transport. For precise delivery of mRNA-LNPs to dendritic cells, we employed a mannose-modified PEGylated lipid that targets mannose receptors. Our results demonstrated that the combination of mannose-directed targeting and pH-mediated endosomal escape significantly enhances antigen translation and expression, leading to a vigorous immune response, as validated by both in vitro and in vivo experiments. This ambidextrous strategy advances the formulation of LNPs for precise mRNA delivery and effective antigen encoding, facilitating the development of mRNA vaccines in the field of antitumor immunology.