Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling
Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling
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使用类脂质材料递送 mRNA 疫苗可通过 Toll 样受体 4 信号传导增强抗肿瘤功效。
DOI：
10.1073/pnas.2005191118
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发表时间：
2021-02-09
影响因子：
11.1
通讯作者：
Xia, Xiaojun
中科院分区：
文献类型：
--
作者：
Zhang, Hongxia;You, Xinru;Xia, Xiaojun
基于信使RNA（mRNA）的肿瘤疫苗的细胞内递送已经显示出引起抗肿瘤免疫的巨大潜力。为了实现稳健的抗肿瘤功效，编码肿瘤抗原的mRNA需要在树突细胞中有效地递送和翻译，同时进行先天免疫刺激以促进抗原呈递。在这里，通过筛选一组阳离子脂质样材料，我们开发了一种具有C1脂质纳米颗粒（LNP）的极简纳米疫苗，该纳米疫苗可以在抗原呈递细胞中有效地递送mRNA，同时Toll样受体4（TLR 4）活化并诱导强大的T细胞活化。C1纳米疫苗通过吞噬作用进入细胞，并显示出有效的mRNA编码的抗原表达和呈递。此外，C1脂质纳米粒本身通过刺激树突状细胞中的TLR 4信号通路诱导炎性细胞因子如IL-12的表达。重要的是，C1 mRNA纳米疫苗在肿瘤预防和治疗性疫苗设置中均表现出显著的抗肿瘤功效。总的来说，我们的工作提出了一种基于C1 LNP的mRNA癌症纳米疫苗，具有有效的抗原表达以及自佐剂特性，这可能为开发用于各种肿瘤类型的癌症免疫疗法提供平台。
Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.