Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited treatment options, largely due to the dense tumor microenvironment and KRAS mutations driving chemoresistance. Targeted co-delivery of small interfering RNA (siRNA) against KRAS (siKRAS) and conventional chemotherapeutics via aptamer-functionalized polymeric nanoparticles (APNPs) offers a promising strategy to enhance therapeutic efficacy.Methods: We developed poly(lactic-co-glycolic acid) (PLGA)-based APNPs surface-conjugated with an RNA aptamer targeting epithelial cell adhesion molecule (EpCAM), overexpressed in PDAC. Nanoparticles co-loaded siKRAS and gemcitabine (GEM) were characterized for size, zeta potential, drug loading, and release kinetics. Cellular uptake, gene silencing, and cytotoxicity were assessed in PANC-1 and BxPC-3 cells. In vivo antitumor efficacy was evaluated in a subcutaneous PDAC xenograft model.Results: APNPs exhibited uniform size (~150 nm), high encapsulation efficiency, and pH-responsive release. Aptamer conjugation significantly enhanced cellular uptake and selective cytotoxicity in EpCAM-positive cells. Co-delivery of siKRAS and GEM achieved >80% KRAS knockdown and synergistic cytotoxicity (combination index Conclusions: EpCAM-targeted APNPs co-delivering siKRAS and GEM represent a potent, selective nanoplatform for PDAC therapy, warranting further translational development.
Keywords
pancreatic ductal adenocarcinoma, aptamer-functionalized nanoparticles, siRNA delivery, KRAS, gemcitabine, targeted therapy, polymeric nanoparticles, EpCAM