In vitro transcribed mRNA constitutes a versatile platform to encode antigens and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged into cationic liposomes (lipoplexes) has proven particularly powerful in achieving effective antitumor immunity in animal models. Yet, T-cell responses to mRNA lipoplexes critically depend on the induction of type I interferons (IFN), potent pro-inflammatory cytokines, which inflict dose-limiting toxicities. Here, we explored an advanced hybrid lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with a trimannose sugar tree as an alternative delivery vehicle for systemic mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely effective in conferring antitumor T-cell immunity upon systemic administration. Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on type I IFN for effective T-cell immunity. This differential mode of action of mRNA lipopolyplexes enabled the incorporation of N1 methyl pseudouridine nucleoside modified mRNA to reduce inflammatory responses without hampering T-cell immunity. This feature was attributed to mRNA lipopolyplexes, as the incorporation of thus modified mRNA into lipoplexes resulted in strongly weakened T-cell immunity. Taken together, we have identified lipopolyplexes containing N1 methyl pseudouridine nucleoside modified mRNA as potent yet low-inflammatory alternatives to the mRNA lipoplexes currently explored in early phase clinical trials.

中文翻译：

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靶向mRNA的树突状细胞脂多聚体结合了强大的抗肿瘤T细胞免疫力和改善的炎性安全性

体外转录的mRNA构成了编码抗原和引发CD8 T细胞反应的多功能平台。已证明包装在阳离子脂质体（脂质复合体）中的mRNA的系统递送在动物模型中实现有效的抗肿瘤免疫特别有效。然而，T细胞对mRNA脂质复合物的反应严重依赖于I型干扰素（IFN）的诱导，这是有效的促炎细胞因子，具有剂量限制性毒性。在这里，我们探索了一种先进的杂种脂质聚合物壳mRNA纳米颗粒（lipopolyplex），其具有三甘露糖树作为系统性mRNA疫苗的替代递送载体。像mRNA脂质复合物一样，mRNA脂质复合物在全身给药后在赋予抗肿瘤T细胞免疫方面非常有效。与mRNA脂质复合物相反，mRNA脂蛋白复合物不依赖I型干扰素进行有效的T细胞免疫。mRNA脂蛋白复合物的这种不同的作用方式使N1甲基伪尿苷核苷修饰的mRNA的掺入能够减少炎症反应，而又不影响T细胞免疫力。该特征归因于mRNA脂质多聚体，因为将如此修饰的mRNA掺入脂质复合体导致T细胞免疫力大大减弱。综上所述，我们已经鉴定出包含N1甲基伪尿苷核苷修饰的mRNA的脂蛋白复合物，是目前在早期临床试验中探索的mRNA脂蛋白的有效而低炎症的替代物。mRNA脂蛋白复合物的这种不同的作用方式使N1甲基伪尿苷核苷修饰的mRNA的掺入能够减少炎症反应，而又不影响T细胞免疫力。该特征归因于mRNA脂质多聚体，因为将如此修饰的mRNA掺入脂质复合体导致T细胞免疫力大大减弱。综上所述，我们已经鉴定出包含N1甲基伪尿苷核苷修饰的mRNA的脂蛋白复合物，是目前在早期临床试验中探索的mRNA脂蛋白的有效而低炎症的替代物。mRNA脂蛋白复合物的这种不同的作用方式使N1甲基伪尿苷核苷修饰的mRNA的掺入能够减少炎症反应，而又不影响T细胞免疫力。该特征归因于mRNA脂质多聚体，因为将如此修饰的mRNA掺入脂质复合体导致T细胞免疫力大大减弱。综上所述，我们已经鉴定出包含N1甲基伪尿苷核苷修饰的mRNA的脂蛋白复合物，是目前在早期临床试验中探索的mRNA脂蛋白的有效而低炎症的替代物。