Messenger RNA (mRNA)‐based vaccines have enormous potential in infectious disease prevention and tumor neoantigen application. However, developing an advanced delivery system for efficient mRNA delivery and intracellular release for protein translation remains a challenge. Herein, a biocompatible biomimetic system is designed using red blood cell‐derived nanoerythrosomes (NER) and black phosphorus nanosheets (BP) for mRNA delivery. BP is covalently modified with polyethyleneimine (PEI), serving as a core to efficiently condense mRNA via electrostatic interactions. To facilitate the spleen targeting of the mRNA‐loaded BP (BPmRNA), NER is co‐extruded with BPmRNA to construct a stable “core–shell” nanovaccine (NER@BPmRNA). The mRNA nanovaccine exhibits efficient protein expression and immune activation via BP‐mediated adjuvant effect and enhanced lysosomal escape. In vivo evaluation demonstrates that the system delivery of mRNA encoding coronavirus receptor‐binding domain (RBD) significantly increases the antibody titer and pseudovirus neutralization effect compared with that of NER without BP assistance. Furthermore, the mRNA extracted from mouse melanoma tissues is utilized to simulate tumor neoantigen delivered by NER@BPmRNA. In the vaccinated mice, BP‐assisted NER for the delivery of melanoma mRNA can induce more antibodies that specifically recognize tumor antigens. Thus, BP‐assisted NER can serve as a safe and effective delivery vehicle in mRNA‐based therapy.

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