Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 6; pp. 1 - 12
• Main Authors: Zhang, Hongxia, You, Xinru, Wang, Xiaojuan, Cui, Lei, Wang, Zining, Feifei Xua, Mengyun Li, Yang, Zhenggang, Liu, Jinyun, Huang, Peng, Kang, Yang, Wu, Jun, Xia, Xiaojun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09-02-2021
• Subjects: Animals; Antineoplastic Agents - immunology; Biological Sciences; Bone Marrow Cells - cytology; Cytokines - metabolism; Dendritic Cells - immunology; Endocytosis; Female; HEK293 Cells; Humans; Immunity, Innate; Lipids - chemistry; Lymphocyte Activation - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Nanoparticles - chemistry; RNA, Messenger - administration & dosage; RNA, Messenger - immunology; Signal Transduction; T-Lymphocytes - immunology; Tissue Distribution; Toll-Like Receptor 4 - metabolism; lipid-like material; self-adjuvant; mRNA nanovaccine; TLR4; cancer immunotherapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2005191118

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.