Lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) vaccineare a promising platform to prevent infectious diseases as demonstrated by the recent success of SARS-CoV-2 mRNA vaccines. To avoid immune recognition and uncontrolled inflammation, nucleoside-modified mRNA is used. However, such modification largely abrogates the innate immune responses that are critical to orchestrating robust adaptive immunity. Here we develop an LNP component—an adjuvant lipidoid—that can enhance the adjuvanticity of mRNA-LNP vaccines. Our results show that partial substitution of ionizable lipidoid with adjuvant lipidoid not only enhanced mRNA delivery, but also endowed LNPs with Toll-like receptor 7/8-agonistic activity, which significantly increased the innate immunity of the SARS-CoV-2 mRNA-LNP vaccine with good tolerability in mice. Our optimized vaccine elicits potent neutralizing antibodies against multiple SARS-CoV-2 pseudovirus variants, strong Th1-biased cellular immunity, and robust B cell and long-lived plasma cell responses. Importantly, this adjuvant lipidoid substitution strategy works successfully in a clinically relevant mRNA-LNP vaccine, demonstrating its translational potential.

脂质纳米颗粒 （LNP） 配制的信使 RNA （mRNA） 疫苗是预防传染病的一个有前途的平台，最近 SARS-CoV-2 mRNA 疫苗的成功证明了这一点。为避免免疫识别和不受控制的炎症，使用核苷修饰的 mRNA。然而，这种修饰在很大程度上消除了对协调强大的适应性免疫至关重要的先天免疫反应。在这里，我们开发了一种 LNP 成分——一种佐剂类脂质——可以增强 mRNA-LNP 疫苗的佐剂性。我们的结果表明，用辅助脂质类化合物部分取代可电离脂质不仅增强了 mRNA 递送，还赋予了 LNP Toll 样受体 7/8 激动活性，这显着提高了 SARS-CoV-2 mRNA-LNP 疫苗的先天免疫力，在小鼠中具有良好的耐受性。我们优化的疫苗可引发针对多种 SARS-CoV-2 假病毒变体的强效中和抗体、强大的 Th1 偏向细胞免疫以及强大的 B 细胞和长寿命浆细胞反应。重要的是，这种辅助脂质替代策略在临床相关的 mRNA-LNP 疫苗中成功发挥作用，展示了其转化潜力。