Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination

TLDR

mRNA vaccines can elicit strong anti‑cancer immunity without genome integration risk or antigen‑selection limits, yet conventional formulations are poorly internalized by antigen‑presenting cells and are rapidly degraded by enzymes. We engineered a lipopolyplex mRNA vaccine comprising a poly‑(β‑amino ester) core encapsulated in an EDOPC/DOPE/DSPE‑PEG lipid shell, which is taken up by dendritic cells through macropinocytosis. The vaccine intrinsically adjuvates dendritic cells by inducing IFN‑β and IL‑12 via TLR7/8, enhances antigen presentation, and reduces lung metastatic B16‑OVA tumor nodules by over 90 %, demonstrating a promising mRNA vaccine platform.

Abstract

mRNA-based vaccines have the benefit of triggering robust anti-cancer immunity without the potential danger of genome integration from DNA vaccines or the limitation of antigen selection from peptide vaccines. Yet, a conventional mRNA vaccine comprising of condensed mRNA molecules in a positively charged protein core structure is not effectively internalized by the antigen-presenting cells. It cannot offer sufficient protection for mRNA molecules from degradation by plasma and tissue enzymes either. Here, we have developed a lipopolyplex mRNA vaccine that consists of a poly-(β-amino ester) polymer mRNA core encapsulated into a 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine/1,2-dioleoyl-sn-glycero-3-phosphatidyl-ethanolamine/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000 (EDOPC/DOPE/DSPE-PEG) lipid shell. This core-shell structured mRNA vaccine enters dendritic cells through macropinocytosis. It displayed intrinsic adjuvant activity by potently stimulating interferon-β and interleukin-12 expression in dendritic cells through Toll-like receptor 7/8 signaling. Dendritic cells treated with the mRNA vaccine displayed enhanced antigen presentation capability. Mice bearing lung metastatic B16-OVA tumors expressing the ovalbumin antigen were treated with the lipopolyplex mRNA, and over 90% reduction of tumor nodules was observed. Collectively, this core-shell structure offers a promising platform for mRNA vaccine development.