mRNAs encoding self-DNA reactive cGAS enhance the immunogenicity of lipid nanoparticle vaccines

TLDR

Nucleic acid‑based vaccines, particularly mRNA delivered in lipid nanoparticles, hold promise for preventing infections and treating cancer. The study aimed to demonstrate that immunostimulatory proteins can be encoded on mRNA within lipid nanoparticles. The authors showed that an active mutant of cGAS (cGAS∆N) delivered via LNP‑encapsulated mRNA acts as a catalytic adjuvant, enhancing durable antigen‑specific IFNγ‑producing T cells and Th1‑biased antibody responses beyond current LNP‑mRNA vaccines, revealing a new strategy for mRNA‑encoded catalytic adjuvants to generate CD8 T cells.

Abstract

Nucleic acid-based vaccines hold promise in preventing infections and treating cancer. The most common use of this technology is to encode antigenic proteins on mRNAs that are delivered to cells via lipid nanoparticle (LNP) formulations. In this study, we discovered that immunostimulatory proteins can also be encoded on mRNAs in LNPs. We found that an active mutant of the enzyme cGAS, referred to as cGAS∆N, acts as a catalytic adjuvant in LNP-encapsulated mRNA vaccines. The delivery of cGAS∆N mRNA via LNPs in combination with antigen mRNA-LNPs led to durable antigen-specific IFNγ-producing T cells that exceeded the efficiency of antigen-LNPs similar to those currently used in the clinic. This strategy did not compromise B cell responses; rather it induced Th1-biased antibody isotypes. This work unveils new vaccine design strategies using mRNA-encoded catalytic adjuvants that could be ideal for generating CD8