The study investigates the therapeutic potential of exosomes in targeting oncogenic KRAS in pancreatic cancer. Exosomes, which are naturally present in the blood, were found to have enhanced retention in circulation compared to liposomes, due to CD47-mediated protection from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D, a common mutation in pancreatic cancer. These exosomes, called iExosomes, showed superior efficacy in targeting oncogenic KRAS compared to liposomes, and their treatment suppressed cancer in multiple mouse models of pancreatic cancer, significantly increasing overall survival. The results suggest that exosomes can be used as a novel approach for direct and specific targeting of oncogenic KRAS in tumors.The study investigates the therapeutic potential of exosomes in targeting oncogenic KRAS in pancreatic cancer. Exosomes, which are naturally present in the blood, were found to have enhanced retention in circulation compared to liposomes, due to CD47-mediated protection from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D, a common mutation in pancreatic cancer. These exosomes, called iExosomes, showed superior efficacy in targeting oncogenic KRAS compared to liposomes, and their treatment suppressed cancer in multiple mouse models of pancreatic cancer, significantly increasing overall survival. The results suggest that exosomes can be used as a novel approach for direct and specific targeting of oncogenic KRAS in tumors.