Intravenous (i‧v.) delivery of vaccines is emerging as an appealing approach to evoke high-quality T-cell responses needed to combat tumors. Messenger RNA (mRNA) holds huge potential to use in vaccination because of its ease of production, intrinsic adjuvant activity and the high versatility in antigen design, but also requires a potent delivery vehicle to enable antigen expression and immune activation. Lipid based nanoparticles (LNP) are currently the clinically most advanced tool to protect mRNA from degradation and efficiently deliver it inside cells. Yet, i‧v administered LNPs generally tend to distribute to the liver. We hypothesized LNPs can be altered to target antigen presenting cells in the spleen and hereby orchestrate specific and durable immune responses against cancer antigens. By using a design of experiment methodology we were able to screen LNPs in a cost and time effective manner. LNP compositions that were evaluated solely differed in the molar ratios of ionizable lipid, phospholipid, cholesterol and PEG-lipid and the choice of the PEG-lipid. Bayesian Regression modeling enabled us to identify LNP compositions conferring maximum immunogenicity upon i‧v. administration. To link LNP compositions to T cell responses and biodistribution, we prepared the same LNPs packaging either the viral oncoprotein E7 as an antigen or Cy-5 labelled luciferase mRNA. The optimized LNP compositions showed increased localization in the spleen (of mice and non-human primates) and uptake by antigen presenting cells. Furthermore, they induced high magnitude CD8 T cell responses that conferred strong antitumor immunity and prolonged survival of TC-1 tumor bearing mice. Mechanistically, type I interferons and phagocytes were found to be essential for eliciting strong T-cell responses. Unexpectedly, we identified B cells as major mediators of the vaccine- elicited T-cell response, revealing a previously undocumented role of these cells in the immune response to mRNA LNPs. Our data highlight the potential of optimizing LNP compositions by tailoring of the molar ratio of the lipids compromising the LNPs and provide insight in the cell types involved in the mRNA LNP-induced immune response. Collectively, our results illustrate the great promise of intravenous mRNA LNP vaccination for the treatment of cancer.