Rationally tailored lipid nanoparticles (LNPs) with efficient and tunable delivery of mRNA in vivo are crucial for mRNA vaccines. Selective expression of antigenic protein in lymphoid tissues/organs could improve the immunostimulatory efficacy and safety of LNPs-based mRNA vaccines. Inspired by the metabolic behavior that long-chain saturated fatty acids tending to enter lymphoid tissue rather than the liver, we developed fatty acid-doped LNPs capable of mediating differential protein expressions in the liver and spleen when administered intravenously. When the molar ratio of saturated fatty acid located 60%–70%, the doped LNPs achieved the spleen selective mRNA translation. The mechanism could be attributed to the different cellular uptake behaviors of saturated fatty acids in hepatocytes. Immunization with a model antigen (ovalbumin) mRNA-loaded spleen selective LNPs, we observed enhanced antigen-specific T cell immune responses, and potent immunotherapeutic and immunoprophylactic efficacy in the mouse lymphoma model. Our natural long-chain saturated fatty acids metabolic characteristics-inspired design of LNPs for spleen-selective mRNA vaccines delivery will provide references for designing mRNA vaccines with high efficacy and safety for tumor immunotherapy.