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

## TL;DR

OncoLRC is a new type of mRNA vaccine delivery system that targets the spleen, activates immune responses, and shows strong potential for cancer treatment.

## Contribution

OncoLRC is a rationally engineered, one-component lipid-mRNA complex that enables efficient spleen-targeted delivery with a low lipid-to-mRNA ratio.

## Key findings

- OncoLRC achieves nearly exclusive spleen-targeting mRNA delivery, outperforming conventional lipid nanoparticle formulations.
- OncoLRC promotes dendritic cell maturation and activates robust antigen-specific immune responses.
- OncoLRC synergizes with immune checkpoint blockade therapy to inhibit tumor growth in a cold tumor model.

## 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.

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.