Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-0856, Japan.
Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
ACS Nano. 2023 Oct 10;17(19):18758-18774. doi: 10.1021/acsnano.3c02251. Epub 2023 Sep 26.
RNA vaccines based on lipid nanoparticles (LNPs) with transcribed mRNA (IVT-mRNA) encapsulated are now a currently successful but still evolving modality of vaccines. One of the advantages of RNA vaccines is their ability to induce CD8 T-cell-mediated cellular immunity that is indispensable for excluding pathogen-infected cells or cancer cells from the body. In this study, we report on the development of LNPs with an enhanced capability for inducing cellular immunity by using an ionizable lipid with a vitamin E scaffold. An RNA vaccine that contained this ionizable lipid and an IVT-mRNA encoding a model antigen ovalbumin (OVA) induced OVA-specific cytotoxic T cell responses and showed an antitumor effect against an E.G7-OVA tumor model. Vaccination with the LNPs conferred protection against lethal infection by using its antigen TgPF. The vitamin E scaffold-dependent type I interferon response was important for effector CD8 T cell differentiation induced by the mRNA-LNPs. Our findings also revealed that conventional dendritic cells (cDCs) were essential for achieving CD8 T cell responses induced by the mRNA-LNPs, while the XCR1-positive subset of cDCs, cDC1 specialized for antigen cross-presentation, was not required. Consistently, the mRNA-LNPs were found to selectively transfect another subset of cDCs, cDC2 that had migrated from the skin to lymph nodes, where they could make vaccine-antigen-dependent contacts with CD8 T cells. The findings indicate that the activation of innate immune signaling by the adjuvant activity of the vitamin E scaffold and the expression of antigens in cDC2 are important for subsequent antigen presentation and the establishment of antigen-specific immune responses.
基于包裹转录信使 RNA（IVT-mRNA）的脂质纳米颗粒（LNPs）的 RNA 疫苗现在是一种成功但仍在不断发展的疫苗模式。RNA 疫苗的一个优势是它们能够诱导 CD8 T 细胞介导的细胞免疫，这对于排除病原体感染细胞或癌细胞至关重要。在这项研究中，我们报告了通过使用具有维生素 E 支架的可离子化脂质来增强诱导细胞免疫能力的 LNPs 的开发。含有这种可离子化脂质和编码模型抗原卵清蛋白（OVA）的 IVT-mRNA 的 RNA 疫苗诱导了 OVA 特异性细胞毒性 T 细胞反应，并显示出对 E.G7-OVA 肿瘤模型的抗肿瘤作用。使用含有其抗原 TgPF 的 LNPs 进行疫苗接种可针对致死性感染提供保护。维生素 E 支架依赖性 I 型干扰素反应对于由 mRNA-LNPs 诱导的效应 CD8 T 细胞分化很重要。我们的研究结果还表明，常规树突状细胞（cDCs）对于由 mRNA-LNPs 诱导的 CD8 T 细胞反应至关重要，而抗原交叉呈递专业化的 cDC1，即 XCR1 阳性 cDC 亚群，并不需要。一致地，发现 mRNA-LNPs 选择性转染另一种 cDC 亚群，即已经从皮肤迁移到淋巴结的 cDC2，在淋巴结中它们可以与 CD8 T 细胞进行疫苗抗原依赖性接触。这些发现表明，维生素 E 支架的佐剂活性和 cDC2 中抗原的表达对随后的抗原呈递和建立抗原特异性免疫反应很重要。
