In this study, we engineer a spleen-selective LNPs-based mRNA vaccine by decoupling the inflammation from cellular immunity mediated cancer immunotherapy and elucidate its potential mechanisms as the molecular structure of ionizable lipid significantly enhances antigen expression and presentation efficiency by improving lysosomal escape efficiency while simultaneously attenuating TLR4-mediated pro-inflammatory signaling activation. The gene discussed is TLR4; the disease is cancer.