Co-delivery of IL-12 mRNA and small-molecule prodrug with lung-tropic lipid nanoparticles for synergistic cancer therapy.

Despite the remarkable success of mRNA vaccines, extrahepatic tissue-specific delivery of therapeutic mRNAs remains challenging. Here, we report a lung-tropic lipid nanoparticles (LNPs) platform that is rationally engineered for simultaneously co-delivering interleukin-12 (IL-12) mRNA and docetaxel prodrug to address the lung metastatic issue. By optimizing a panel of synthetic cationic lipids, we identified N112 as the optimal cationic lipid, with N112-DOTAP LNP formulation demonstrating moderately enhanced transfection efficiency in lung tissue compared to the benchmark MC3-DOTAP LNP. Moreover, N112-DOTAP LNP has a uniform particle size and high encapsulation efficiency for both therapeutic payloads. In a B16F10 lung metastasis model, the combination therapy demonstrated superior antitumor efficacy, reducing tumor nodules compared to the saline treatment, while maintaining the safety profile with no significant body weight loss or organ toxicity. This study provides a robust therapeutic strategy for mRNA-based combination cancer therapy.