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

OncoLRC, a one‐component lipid‐mRNA complex, enables efficient spleen‐targeted delivery at an exceptionally low lipid‐to‐mRNA mass ratio (1.5:1), robustly activates immune responses, inhibits tumor growth, and synergizes with checkpoint blockade, presenting a next‐generation platform for mRNA vaccines. Abstract 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 (OncoLRCOVA) 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, OncoLRCOVA 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, OncoLRCOVA 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. OncoLRC, a one-component lipid-mRNA complex, enables efficient spleen-targeted delivery at an exceptionally low lipid-to-mRNA mass ratio (1.5:1), robustly activates immune responses, inhibits tumor growth, and synergizes with checkpoint blockade, presenting a next-generation platform for mRNA vaccines. Abstract 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. Advanced Science, EarlyView.