International Journal of Nanomedicine (Nov 2024)
Nasal mRNA Nanovaccine with Key Activators of Dendritic and MAIT Cells for Effective Against Lung Tumor Metastasis in Mice Model
Abstract
Ang Li,1,* Xushan Cai,2,* Dong Li,1,* Yimin Yu,1 Chengyu Liu,1 Jie Shen,1 Jiaqi You,3 Jianou Qiao,3 Feng Wang4 1Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, School of Life Science and Technology, Tongji University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Shanghai Jiading Maternal and Child Health Hospital, Shanghai, People’s Republic of China; 3Department of Respiratory, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Thoracic Surgery, Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ang Li, Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, School of Life Science and Technology, Tongji University, No. 389 Xincun Road, Shanghai, 200065, People’s Republic of China, Email [email protected] Feng Wang, Department of Thoracic Surgery, Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Shanghai, 200011, People’s Republic of China, Email [email protected]: Lung metastasis is a leading cause of cancer-related death. mRNA-based cancer vaccines have been demonstrated to be effective at inhibiting tumor growth. Intranasal immunization has emerged as a more effective method of inducing local immune responses against cancer cells in the lungs.Methods: An innovative layered double hydroxide- and 5-OP-RU–based mRNA nanovaccine (Mg/Al LDH-5-OP-RU/mRNA) was synthesized via coprecipitation. The particle size distribution and zeta potential were measured, and the nanovaccine was observed by transmission electron microscopy. The functions and properties of the nanovaccine were evaluated via an mRNA-targeted delivery assay and measurement of dendritic cell (DC) and mucosa-associated invariant T (MAIT) cell maturation and activation. In addition, the cytotoxicity, antigen-specific T cell activation, cytokines, protective ability, and therapeutic ability of the nanovaccine were assessed in a mouse tumor model. Further, the immune cell composition was evaluated in tumors.Results: The Mg/Al LDH-5-OP-RU/mRNA nanovaccine was efficiently delivered into lung-draining mediastinal lymph nodes (MLNs), and it activated dendritic cells (DCs) and mucosa-associated invariant T (MAIT) cells after intranasal administration. Moreover, the optimized dual-activating mRNA nanovaccine efficiently transfected DC cells and expressed antigen proteins in DC cells. An HPV-associated tumor model revealed that the intranasal delivery of the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine significantly prevented the lung metastasis of tumors and had a therapeutic effect on established metastatic tumor nodules in the lungs. Mechanistically, the enhanced activation of DC and MAIT cells induced by the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine increased the production of immune-stimulating cytokines and decreased the secretion of immunosuppressive cytokines, which led to the expansion and activation of memory T cells targeting the E7 antigen, a reduction in the population of neutrophils, and differentiation of tumor -associated macrophages to the M1 phenotype in the lungs.Conclusion: These results highlight the potential of the innovative nasal mRNA nanovaccine for both preventing and treating tumor metastasis in the lungs.Keywords: mRNA nanovaccine, layered double hydroxide, 5-OP-RU, dendritic cells, Mucosa-associated invariant T cells, lung metastasis
