A Rationally Engineered Spleen‐Tropic One‐Component Lipid‐mRNA Complex (OncoLRC) for Cancer Vaccines

mRNA vaccines offer great potential for cancer immunotherapy, yet efficient delivery of antigen-encoding mRNA to antigen-presenting cells (APCs) in lymphoid organs remains a significant challenge. Here, OncoLRC is introduced, a rationally engineered, spleen-tropic, one-component lipid-mRNA complex that selectively delivers mRNA to splenic APCs following systemic administration. Through a systemic screening and optimization process, a dimethylamino (DMA)-lipidoid-based OncoLRC formulation that achieves nearly exclusive spleen-targeting mRNA delivery, outperforming its conventional four-component lipid nanoparticle (LNP) formulation counterpart has been developed. Notably, OncoLRC requires a reduced lipid-to-mRNA weight ratio of 1.5:1 compared to the typical 10:1 ratio in standard LNPs. OncoLRC formulated with ovalbumin (OVA) mRNA (OncoLRC^OVA) promotes dendritic cell (DC) maturation and activation, eliciting robust antigen-specific immune responses. Mechanistic studies suggest that splenic delivery is mediated primarily via macropinocytosis. Moreover, OncoLRC^OVA enhances the secretion of endogenous cytokines such as IL-12, further stimulating T cell activation and cytotoxic activity. In the B16F10-OVA cold tumor model, OncoLRC^OVA demonstrates strong prophylactic antitumor efficacy and exhibits a profound synergistic effect when combined with immune checkpoint blockade therapy, leading to significant tumor growth inhibition. Collectively, our findings establish OncoLRC as a simple yet effective APC-targeted mRNA delivery platform, highlighting its potential as a next-generation mRNA cancer vaccine system.