Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects.

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs. Additionally, we applied cleavable PEG-lipids in mRNA vaccines for the first time and found this conducive to cellular uptake and DC targeting. In summary, SA-modified mRNA vaccines targeted DCs efficiently, and showed significantly higher EEs/lysosomal escape efficiency (90% vs 50%), superior tumor treatment effect, and lower side effects than commercially formulated mRNA vaccines. The SA-modified mRNA vaccine prepared by microfluidic mixture synchronously realizes DCs targeted and efficient EEs and lysosome escape, activates the immune system to eliminate tumors. [Display omitted] • Simultaneously achieving DC targeting and efficient endosomal/lysosomal escape. • First to apply sialic acid- lipid derivative and cleavable PEG-lipid on mRNA LNPs. • Constructed a new computational model to evaluate the transfection efficiency of mRNA delivery vectors. • SA modification significantly improved the antitumor efficacy of mRNA vaccine, and has fewer side effects. [ABSTRACT FROM AUTHOR]