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.

中文翻译：

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掺入锰氧化物的杂化脂质纳米颗粒通过氧气产生和 STING 激活放大 mRNA 疫苗的效力


信使 RNA （mRNA） 疫苗在治疗人类疾病方面显示出巨大的潜力;然而，由于 mRNA 翻译过程中活性氧的诱导，它们的广泛应用受到限制，这大大降低了翻译效率。在此，我们提出了一种稳健的策略，能够通过促进干扰素基因的 mRNA 翻译和刺激剂 （STING） 激活来显着提高 mRNA 疫苗的功效。该策略需要将小尺寸氧化锰纳米颗粒 （Mn₃O₄ NPs） 与脂质纳米颗粒 （LNP） 共组装，作为制造 mRNA 疫苗的杂交递送载体 （MnLNPs）。获得的 MnLNP 熟练地清除 mRNA 翻译过程中产生的活性氧 （ROS） 并促进氧气的产生，从而促进三磷酸腺苷 （ATP） 合成并增强 mRNA 翻译。此外，MnLNPs 通过激活 cGAS-STING 通路有效促进树突状细胞的抗原呈递和成熟。体内研究表明，与 LNP 相比，由 MnLNPs 制备的 mRNA 疫苗显着增强了抗原编码 mRNA 的翻译，从而具有卓越的抗肿瘤疗效。通过与免疫检查点阻断协同作用，MnLNPs@mRNA 的肿瘤抑制能力得到进一步促进，强调了基于 MnLNPs 的 mRNA 疫苗是癌症免疫治疗中非常有前途的途径。