Messenger RNA (mRNA) vaccines are gradually becoming a promising treatment method for tumor immunotherapy. The efficient antigen presentation capability in tumor immunotherapy through the targeted mRNA delivery system using spleen dendritic cells (DCs) is very important, but it remains a significant challenge. This study synthesized a library of ionizable lipids similar to a binary system (referred to as H-type ionizable lipids, HIL) for the construction of mRNA-coated nanoparticles (mRNA/HNPs) for in vivo mRNA delivery. The structure-activity relationship (SAR) analysis indicated that the spleen-targeted transfection efficiency of mRNA was highly correlated with the apparent pKa value of mRNA/HNP after intravenous injection. After formulation screening, an optimized mRNA/HNP based on H18 lipid (mRNA/H18NPs) was successfully prepared, with an average particle size of 124.4±2.4 nanometers, and a multi-layered concentric nanostructure. Interestingly, without any ligand modification, mOVA/H18NPs showed spleen-targeted mRNA transfection of DCs, significantly increasing the number of IFN-γ+ CD8+ T cells and effector memory CD8+ T cells. Moreover, the in vivo results indicated that mRNA/H18NPs coated with antigen-coding mRNA (including ovalbumin OVA) or tyrosinase-related protein 2 (Trp2) effectively activated antigen-specific CD8+ T cells and showed significant anti-tumor efficacy in B16-OVA and B16F10 tumor-bearing mouse models after intravenous injection. Especially, unlike the mOVA/MC3-LNPs group, mOVA/H18NPs, when used as a preventive cancer vaccine in the B16-OVA tumor-bearing mouse model, exhibited complete inhibition of tumor progression. These findings highlight the mRNA/H18NPs as a promising spleen dendritic cell-targeted delivery system for mRNA vaccines.

This study was published in Bioactive Materials under the title "Splenic dendritic cell-targeting mRNA transfection of H-type ionizable lipid-based LNPs for enhancing tumor immunotherapy".

Reference: DOI: 10.1016/j.bioactmat.2026.02.018