带有杂环脂质的mRNA疫苗递送通过STING介导的免疫细胞激活提高抗肿瘤功效，这一成果由美国麻省理工学院Daniel G. Anderson团队近期取得。2019年9月30日，国际知名学术期刊《自然—生物技术》在线发表了这一成果。

研究人员开发了可电离的脂质样物质的组合文库，以鉴定可促进体内mRNA递送并提供有效和特异性免疫激活的mRNA递送载体。使用三维多组分反应系统，研究人员合成并评估了1000多种脂质制剂的疫苗潜力。最佳候选制剂可诱导强烈的免疫反应，并能够在体内肿瘤模型中抑制肿瘤生长并延长黑色素瘤和人乳头瘤病毒E7肿瘤的生存期。表现最佳的脂质有一个共同的结构：不饱和脂质尾部、二氢咪唑连接基和环状胺头基团。这些制剂通过STING通路而不是Toll样受体来诱导抗原呈递细胞成熟，并导致有限的全身细胞因子表达和增强的抗肿瘤功效。

据悉，治疗性mRNA疫苗可以递送完整抗原，这比多肽疫苗更具优势。然而，最佳功效既需要细胞内递送从而让抗原翻译，又需要适当的免疫激活。

附：英文原文

Title: Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation

Author: Lei Miao, Linxian Li, Yuxuan Huang, Derfogail Delcassian, Jasdave Chahal, Jinsong Han, Yunhua Shi, Kaitlyn Sadtler, Wenting Gao, Jiaqi Lin, Joshua C. Doloff, Robert Langer, Daniel G. Anderson

Issue&Volume: 2019-09-30

Abstract: Therapeutic messenger RNA vaccines enable delivery of whole antigens, which can be advantageous over peptide vaccines. However, optimal efficacy requires both intracellular delivery, to allow antigen translation, and appropriate immune activation. Here, we developed a combinatorial library of ionizable lipid-like materials to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation. Using a three-dimensional multi-component reaction system, we synthesized and evaluated the vaccine potential of over 1,000 lipid formulations. The top candidate formulations induced a robust immune response, and were able to inhibit tumor growth and prolong survival in melanoma and human papillomavirus E7 in vivo tumor models. The top-performing lipids share a common structure: an unsaturated lipid tail, a dihydroimidazole linker and cyclic amine head groups. These formulations induce antigen-presenting cell maturation via the intracellular stimulator of interferon genes (STING) pathway, rather than through Toll-like receptors, and result in limited systemic cytokine expression and enhanced anti-tumor efficacy. 

DOI: 10.1038/s41587-019-0247-3

Source:https://www.nature.com/articles/s41587-019-0247-3