Lung-targeted delivery of TRAIL and BAK mRNA by optimized lipid nanoparticles for in vivo lung metastasis

The direct expression of therapeutic genes in tumor tissue is a promising cancer therapy, but it has been limited by delivery issues. Herein, we fabricated optimized mRNA-encapsulating lipid nanoparticles (LNPs) and applied them to lung-targeted delivery of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and BCL2-antagonist/killer (BAK) mRNAs for lung metastasis therapy. mRNA and LNPs were optimized by in vitro and in vivo experiments to achieve the highest expression in lung metastasis tissue. The selected formulation containing luciferase mRNA generated an intense luminescence signal in the lung while using a low ratio (15 %) of cationic DOTAP, which was advantageous to reduce cytotoxicity. The TRAIL and BAK mRNAs were encapsulated in lung-targeting LNPs (LtNPs) together and delivered to lung metastasis tumor tissue. Through the in vivo transfection and generation of TRAIL and BAK, apoptosis could be induced via the extrinsic death receptor and intrinsic mitochondrial pathway simultaneously. Intravenous injections of the optimized LtNPs containing TRAIL and BAK mRNAs effectively suppressed tumors in a mouse model of A549 lung metastasis. These overall results demonstrate the promising potential of mRNA-LNPs to directly deliver therapeutic genes to tumor tissue for cancer therapy.