EpCAM-Targeted 3WJ RNA Nanoparticle Harboring Delta-5-Desaturase siRNA Inhibited Lung Tumor Formation via DGLA Peroxidation

Knocking down delta-5-desaturase (D5D) expression by D5D small interfering RNA (siRNA) has been reported that could redirect the cyclooxygenase-2 (COX-2)-catalyzed dihomo-γ-linolenic acid (DGLA) peroxidation from producing prostaglandin E2 to 8-hydroxyoctanoic acid (8-HOA), resulting in the inhibition of colon and pancreatic cancers. However, the effect of D5D siRNA on lung cancer is still unknown. In this study, by incorporating epithelial cell adhesion molecule (EpCAM) aptamer and validated D5D siRNA into the innovative three-way junction (3WJ) RNA nanoparticle, target-specific accumulation and D5D knockdown were achieved in the lung cancer cell and mouse models. By promoting the 8-HOA formation from the COX-2-catalyzed DGLA peroxidation, the 3WJ-EpCAM-D5D siRNA nanoparticle inhibited lung cancer growth in vivo and in vitro. As a potential histone deacetylases inhibitor, 8-HOA subsequently inhibited cancer proliferation and induced apoptosis via suppressing YAP1/TAZ nuclear translocation and expression. Therefore, this 3WJ-RNA nanoparticle could improve the targeting and effectiveness of D5D siRNA in lung cancer therapy. [Display omitted] Despite the high expression of cyclooxygenase-2, the clinical outcomes of cyclooxygenase-2 inhibitors remain unsatisfactory for cancer therapy. We utilized epithelial cell adhesion molecule-targeted three-way junction-RNA nanoparticle to deliver delta-5-desaturase siRNA to lung cancer cells, resulting in the shift on the cyclooxygenase-2 pathway to achieve cancer cell death.