Manganese Oxide-Incorporated\nHybrid Lipid Nanoparticles\nAmplify the Potency of mRNA Vaccine via Oxygen Generation and STING\nActivation

Messenger RNA (mRNA) vaccines have exhibited enormous\npotential\nin the treatment of human diseases; however, their widespread applications\nare curtailed by the induction of reactive oxygen species during mRNA\ntranslation, which greatly compromises the translation efficiency.\nHerein, we present a robust strategy with the capability to substantially\nenhance the efficacy of the mRNA vaccine through promoting mRNA translation\nand stimulator of interferon genes (STING) activation. The strategy\nentails the coassembly of small-sized manganese oxide nanoparticles\n(Mn<sub>3</sub>O<sub>4</sub> NPs) with lipid nanoparticles (LNPs)\nas the hybrid delivery vehicle (MnLNPs) for the fabrication of mRNA\nvaccine. The acquired MnLNPs proficiently scavenge reactive oxygen\nspecies (ROS) produced during mRNA translation and facilitate oxygen\nproduction, thereby boosting adenosine triphosphate (ATP) synthesis\nand augmenting mRNA translation. Furthermore, MnLNPs effectively bolster\nthe antigen presentation and maturation of dendritic cells by activating\nthe cGAS-STING pathway. <i>In vivo</i> studies demonstrate\nthat mRNA vaccine prepared from MnLNPs markedly enhances the translation\nof antigen-encoding mRNA compared to LNPs, leading to superior antitumor\nefficacy. The tumor-suppressive capabilities of MnLNPs@mRNA are further\npromoted by synergizing with immune checkpoint blockade, underscoring\nMnLNPs-based mRNA vaccine as an exceptionally promising avenue in\ncancer immunotherapy.