Herein, we report a design for lipid nanoparticles (LNPs) that specifically delivers mRNA to splenic immune cells post intravenous administration for potential anticancer vaccination applications. A diverse library of ionizable lipids was screened in vivo, in combination with various helper lipids, where the composition of LNPs was tweaked to control their in vivo performance. The biodistribution of the LNPs was then investigated at both organ and sub-organ levels. Subsequently, the LNPs were recruited to deliver an anticancer mRNA-based vaccine to mice. The in vivo tropism of the LNPs was dramatically affected by the chemical structure of the ionizable lipids in question, where a model lipid, CL15H6, was recognized as displaying high affinity for the spleen. Further optimization of the composition of the LNPs enabled highly efficient and spleen-selective mRNA delivery, where the optimized CL15H6 LNPs demonstrated a high capacity for homing to splenic antigen-presenting cells (APCs). Furthermore, loading the LNPs with a low dose of ovalbumin-encoding mRNA (mOVA), as a model antigen, protected the mice against OVA-expressing tumor challenges and suppressed the tumor growth in tumor-bearing mice by similar to 75%, which was superior to the results of a clinically-relevant formulation. The CL15H6 LNPs proved to be biosafe upon either acute dose escalation or repeated administrations. The novel and scalable platform reported herein is promising for clinical translation as a neoantigen vaccine.