mRNA vaccine-based cancer immunotherapy requires innate immune activation followed by potent cellular immunity. Vectors of lipid nanoparticles (LNPs) with proinflammatory properties activate the innate immune pathway, while excessive inflammatory response of mRNA-LNPs vaccine often results in systemic inflammation, compromising its therapeutic safety.Here, we engineered a spleen-selective mRNA-LNPs (mRNA-sLNPs) vaccine by decoupling the excessive inflammation from strong cellular immunity through ionizable lipids substituting for potent cancer immunotherapy.The mRNA-sLNPs vaccine with reduced inflammation achieved superior mRNA translation in the spleen and enhanced antigen-specific cellular immune responses. Mechanistically, the optimized mRNA-sLNPs vaccine amplified lysosomal escape and boosted antigen presentation with moderate co-stimulatory molecule expression by mitigating TLR4/MyD88/NF-κB signaling and pro-inflammatory cytokine secretion. In therapeutic mouse models, the engineered mRNA vaccine significantly inhibited both the growth of subcutaneous B16F10-OVA melanomas and the development of lung metastases following intravenous injection of B16F10-OVA cells with augmented infiltration of CD4and CD8T cells in the tumor microenvironment.Our findings might redefine the design principles of mRNA-LNPs vaccine as diminishing the inflammation of LNPs does not compromise cellular immunity, offering a clinically translatable strategy to advance mRNA vaccines for cancer immunotherapy. Rationale: Methods: Results: Conclusion: + +
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