CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China.
Department of Biomaterials, Key Laboratory of Biomedical Engineering of Fujian Province, College of Materials, Xiamen University, Xiamen, Fujian, 361005, China.
Adv Mater. 2022 May;34(20):e2109984. doi: 10.1002/adma.202109984. Epub 2022 Apr 15.
Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. In this work, bacteria-derived outer membrane vesicles (OMVs) are employed as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL). OMV-LL can rapidly adsorb box C/D sequence-labelled mRNA antigens through L7Ae binding (OMV-LL-mRNA) and deliver them into dendritic cells (DCs), following by the cross-presentation via listeriolysin O-mediated endosomal escape. OMV-LL-mRNA significantly inhibits melanoma progression and elicits 37.5% complete regression in a colon cancer model. OMV-LL-mRNA induces a long-term immune memory and protects the mice from tumor challenge after 60 days. In summary, this platform provides a delivery technology distinct from lipid nanoparticles (LNPs) for personalized mRNA tumor vaccination, and with a "Plug-and-Display" strategy that enables its versatile application in mRNA vaccines.
治疗性 mRNA 疫苗接种是触发抗肿瘤免疫的一种有吸引力的方法。然而，用于定制肿瘤疫苗的 mRNA 递送技术仍然有限。在这项工作中，细菌衍生的外膜囊泡（OMV）通过基因工程被用作 mRNA 递送平台，通过表面修饰 RNA 结合蛋白 L7Ae 和溶酶体逃逸蛋白李斯特菌溶血素 O（OMV-LL）进行修饰。OMV-LL 可以通过 L7Ae 结合（OMV-LL-mRNA）快速吸附带有框 C/D 序列标记的 mRNA 抗原，并将其递送至树突状细胞（DC）中，随后通过李斯特菌溶血素 O 介导的内体逃逸进行交叉呈递。OMV-LL-mRNA 显著抑制黑色素瘤的进展，并在结肠癌模型中引发 37.5%的完全消退。OMV-LL-mRNA 诱导长期免疫记忆，并在 60 天后保护小鼠免受肿瘤挑战。总之，该平台为个性化 mRNA 肿瘤疫苗接种提供了一种与脂质纳米颗粒（LNPs）不同的递送技术，并采用了“即插即用”策略，使其在 mRNA 疫苗中的应用具有多功能性。
