Cationic Lipid-Assisted Polymeric Nanoparticle Mediated GATA2 siRNA Delivery for Synthetic Lethal Therapy of KRAS Mutant Non-Small-Cell Lung Carcinoma

Synthetic lethal interaction provides a conceptual framework for the development of wiser cancer therapeutics. In this study, we exploited a therapeutic strategy based on the interaction between GATA binding protein 2 (GATA2) downregulation and the KRAS mutation status by delivering small interfering RNA targeting GATA2 (si<i>GATA2</i>) with cationic lipid-assisted polymeric nanoparticles for treatment of non-small-cell lung carcinoma (NSCLC) harboring oncogenic KRAS mutations. Nanoparticles carrying si<i>GATA2</i> (NP<sub>si<i>GATA2</i></sub>) were effectively taken up by NSCLC cells and resulted in targeted gene suppression. NP<sub>si<i>GATA2</i></sub> selectively inhibited cell proliferation and induced cell apoptosis in KRAS mutant NSCLC cells. However, this intervention was harmless to normal KRAS wild-type NSCLC cells and HL7702 hepatocytes, confirming the advantage of synthetic lethality-based therapy. Moreover, systemic delivery of NP<sub>si<i>GATA2</i></sub> significantly inhibited tumor growth in the KRAS mutant A549 NSCLC xenograft murine model, suggesting the therapeutic promise of NP<sub>si<i>GATA2</i></sub> delivery in KRAS mutant NSCLC therapy.