Neoantigens　are　emerging　as　attractive　targets　to　develop　personalized　cancer　vaccines,　but　their　immunization　efficacy　is　severely　hampered　by　their　restricted　accessibility　to　lymphoid　tissues　where　immune　responses　are　initiated.　Leveraging　the　capability　of　red　blood　cells　(RBCs)　to　capture　and　present　pathogens　in　peripheral　blood　to　the　antigen-presenting　cells　(APCs)　in　spleen,　we　developed　a　RBC-driven　spleen　targeting　strategy　to　deliver　DNA　vaccine　encoding　hepatocellular　carcinoma　(HCC)　neoantigen.　The　DNA　vaccine-encapsulating　polymeric　nanoparticles　that　were　intentionally　hitchhiked　on　the　preisolated　RBCs　could　preferentially　accumulate　in　the　spleen　to　promote　the　neoantigen　expression　by　APCs,　resulting　in　the　burst　of　neoantigen-specific　T-cell　immunity　to　prevent　tumorigenesis　in　a　personalized　manner,　and　slow　down　tumor　growth　in　the　established　aggressively　growing　HCC.　Remarkably,　when　combined　with　anti-PD-1,　the　vaccine　achieved　complete　tumor　regression　and　generated　a　robust　systemic　immune　response　with　long-term　tumor-specific　immunological　memory,　which　thoroughly　prevented　tumor　recurrence　and　spontaneous　lung　metastasis.　This　study　offers　a　prospective　strategy　to　develop　personalized　neoantigen　vaccines　for　augmenting　cancer　immunotherapy　efficiency　in　immune　“cold”　HCC.　©　2023　The　Authors.　Published　under　the　terms　of　the　CC　BY　4.0　license.