Here, we show a universal anti-cancer vaccine, based on antigen-mRNA-loaded self-assembled polyplex nanocarrier. The establishment of antigen-specific T-cells, as consequence of the vaccination, performed following a subcutaneous route of administration, was confirmed by detection of IFN-γ/IL-2 producing T-cells in the spleen of the treated mice. Moreover, a high release of Th1-releated IgG isotypes (IgG2b and IgG2c) was observed, indicating a predominantly Th1 response. Finally, OVA-mRNA-based vaccine formulation has been employed for the treatment of melanoma lung metastasis of B16-OVA challenged mice, inducing a marked reduction of metastatic nodules up to 93%. Ascertained that any polypeptide-based antigen can be encoded as RNA, potentially our platform can represent a universal strategy suitable for the development of any mRNA-based vaccine.