Exosomes facilitate therapeutic targeting of oncogenic Kras in pancreatic cancer. The study demonstrates that exosomes, which are naturally present in the blood, can be engineered to carry siRNA or shRNA targeting oncogenic Kras (G12D), a common mutation in pancreatic cancer. Compared to liposomes, exosomes show enhanced efficacy in targeting Kras due to CD47-mediated protection from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic Kras (G12D). These iExosomes showed enhanced retention in circulation and targeted pancreatic cancer cells more effectively than liposomes. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. The study highlights the potential of exosomes as a novel approach for direct and specific targeting of oncogenic Kras in tumors. Exosomes were found to be more effective than liposomes in delivering RNAi to pancreatic cancer cells, and their ability to evade phagocytosis was attributed to CD47 on their surface. Additionally, oncogenic RAS was shown to enhance macropinocytosis, which facilitated exosome uptake by pancreatic cancer cells. The study also demonstrated that iExosomes could suppress Kras expression in pancreatic tumors and improve survival in mouse models. The results suggest that exosomes could be a promising therapeutic approach for pancreatic cancer due to their ability to evade immune clearance and efficiently deliver RNAi to target cells.Exosomes facilitate therapeutic targeting of oncogenic Kras in pancreatic cancer. The study demonstrates that exosomes, which are naturally present in the blood, can be engineered to carry siRNA or shRNA targeting oncogenic Kras (G12D), a common mutation in pancreatic cancer. Compared to liposomes, exosomes show enhanced efficacy in targeting Kras due to CD47-mediated protection from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic Kras (G12D). These iExosomes showed enhanced retention in circulation and targeted pancreatic cancer cells more effectively than liposomes. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. The study highlights the potential of exosomes as a novel approach for direct and specific targeting of oncogenic Kras in tumors. Exosomes were found to be more effective than liposomes in delivering RNAi to pancreatic cancer cells, and their ability to evade phagocytosis was attributed to CD47 on their surface. Additionally, oncogenic RAS was shown to enhance macropinocytosis, which facilitated exosome uptake by pancreatic cancer cells. The study also demonstrated that iExosomes could suppress Kras expression in pancreatic tumors and improve survival in mouse models. The results suggest that exosomes could be a promising therapeutic approach for pancreatic cancer due to their ability to evade immune clearance and efficiently deliver RNAi to target cells.