mRNA Delivery with Lipopolymers to Rejuvenate TRAIL Therapy for Lung Cancer Treatment

Abstract Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) has long been identified as a promising therapeutic due to its ability to induce apoptosis selectively in cancer cells. However, poor stability and rapid clearance of the administered TRAIL protein in circulation have hampered its clinical development. With recent advances in the mRNA technology, this study explored the potential of a lung cancer therapy by delivering TRAIL mRNA using lipopolymers. Here, we show that a leading cationic lipopolymer (mRNA-Fect) can package mRNA into nanoparticles (ζ-potential +14.9 to −8.6 mV with a 200−400 nm diameter, as observed by DLS measurement), thereby enhancing transfection efficiency in lung cancer cells. When tested with an mRNA encoding the reporter GFP gene (m-GFP), the lipopolymer induced GFP expression as early as 4 hours, reaching optimal expression by 24 hours, with a high transfection efficiency in lung cancer cells (GFP-positive population: 50−80%). Delivering an m-TRAIL led to TRAIL protein secretion as early as 2 hours post-transfection, significantly reducing viability (∼80%) and activating caspase-3/-7 in lung cancer cells. The lipopolymer successfully expressed reporter genes following intramuscular, subcutaneous, and intravenous administration in animal models. Furthermore, delivery of m-TRAIL suppressed tumor growth in a local lung cancer xenograft model, demonstrating therapeutic potential in the absence of any adverse effects. We conclude that mRNA-Fect-formulated m-TRAIL could be a potent therapy of lung cancers, showing promise for broader therapeutic applications in the future.