Nasal mRNA Nanovaccine with Key Activators of Dendritic and MAIT Cells for Effective Against Lung Tumor Metastasis in Mice Model.

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Lung metastasis is a leading cause of cancer-related death. mRNA-based cancer vaccineshavebeendemonstrated 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. An innovative layered double hydroxide- and 5-OP-RU-basedmRNA 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. The Mg/Al LDH-5-OP-RU/mRNA nanovaccine was efficientlydelivered 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 nanovaccineefficiently transfectedDC cellsand expressed antigenproteinsin DC cells. An HPV-associated tumor model revealed that the intranasal deliveryof the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccinesignificantly prevented the lung metastasis of tumors and had a therapeutic effect on establishedmetastatic tumor nodulesin 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. These results highlight the potential of the innovativenasal mRNA nanovaccine for both preventing and treating tumor metastasis in the lungs.