Messenger RNA (mRNA)-based vaccines have great potential in cancer treatment. However, poor lymphatic transport, insufficient targeted delivery, intracellular degradation and insufficient immune response without adjuvants limit the application of mRNA vaccines. Herein, a novel mRNA nanovaccine (HM@MnO-mRNA) was constructed by ovalbumin (OVA) mRNA-loaded MnO encapsulation with a hybrid membrane (HM) of dendritic cells (DCs) and bacterial membrane for enhancing cancer immunotherapy. In vitro results indicated that HM@MnO-mRNA nanovaccine could target DC2.4 cells, achieve lysosomal escape to enhance the expression of antigen, leading to the efficient antigen presentation and the activation of DC2.4 cells. In vivo results demonstrated that HM@MnO-mRNA nanovaccine could target and retain in lymph nodes (LNs), continuously stimulate antigen presentation, and thus trigger a strong T cell mediated immune response. The prepared nanovaccine could effectively prevent and control the occurrence and development of B16-OVA subcutaneous tumors. This study will provide a new mRNA cancer vaccine delivery platform for cancer immunotherapy.