Manganese Oxide-Incorporated Hybrid Lipid Nanoparticles Amplify the Potency of mRNA Vaccine via Oxygen Generation and STING Activation.

Abstract

Messenger RNA (mRNA) vaccines have exhibited enormous potential in the treatment of human diseases; however, their widespread applications are curtailed by the induction of reactive oxygen species during mRNA translation, which greatly compromises the translation efficiency. Herein, we present a robust strategy with the capability to substantially enhance the efficacy of the mRNA vaccine through promoting mRNA translation and stimulator of interferon genes (STING) activation. The strategy entails the coassembly of small-sized manganese oxide nanoparticles (Mn₃O₄ NPs) with lipid nanoparticles (LNPs) as the hybrid delivery vehicle (MnLNPs) for the fabrication of mRNA vaccine. The acquired MnLNPs proficiently scavenge reactive oxygen species (ROS) produced during mRNA translation and facilitate oxygen production, thereby boosting adenosine triphosphate (ATP) synthesis and augmenting mRNA translation. Furthermore, MnLNPs effectively bolster the antigen presentation and maturation of dendritic cells by activating the cGAS-STING pathway. In vivo studies demonstrate that mRNA vaccine prepared from MnLNPs markedly enhances the translation of antigen-encoding mRNA compared to LNPs, leading to superior antitumor efficacy. The tumor-suppressive capabilities of MnLNPs@mRNA are further promoted by synergizing with immune checkpoint blockade, underscoring MnLNPs-based mRNA vaccine as an exceptionally promising avenue in cancer immunotherapy.