Lipid Nanoparticle–Encapsulated mRNAs Encoding Tumor-Specific Toxin Proteins Selectively Target Cancer Cells and Stimulate T-cell Infiltration

Abstract Treatment with mRNA-based therapeutics represents a potential strategy for improving outcomes of diverse diseases. Tumor-specific toxins might represent ideal candidates for mRNA-based cancer therapeutics. In this study, we investigated the antitumor potential of lipid nanoparticle (LNP)–encapsulated mRNA encoding the tumor-specific toxin protein neutrophil elastase (ELANE) or porcine pancreatic elastase (PPE). Treatment with either ELANE or PPE mRNA-LNP selectively killed various cancer cell types but not noncancer cells in vitro. Furthermore, ELANE and PPE mRNA-LNP administration significantly inhibited tumor growth in vivo and induced CD8+ T-cell infiltration, whereas no acute toxicity was observed in mice. Several additional elastases from different species were also effective against cancer cells. Altogether, these data support further development of tumor-specific toxin protein mRNA-LNP as a therapeutic strategy for cancer. Significance: Treatment with lipid nanoparticle-encapsulated mRNA encoding tumor-specific toxin proteins reduces tumor growth and activates antitumor immunity, providing an alternative approach for treating tumors that are resistant or unresponsive to immunotherapy.