Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes. Exosomes improve the delivery of siRNA to mutant KRAS in the pancreatic tumours and bypass immune clearance better than artificial liposomes, probably owing to enhanced macropinocytocis and presence of CD47 on exosomes, respectively. Mutant KRAS is a common driver of pancreatic cancer, and decreasing its expression with siRNA is a potential strategy to forestall pancreatic tumour growth. To improve delivery of short interfering RNA to the pancreas, Raghu Kalluri and colleagues harness exosomes and show that these endogenous vesicles can bypass immune clearance better than artificial liposomes, probably owing to expression of CD47 in their membrane. The iExosomes are uptaken preferentially by pancreatic tumour cells. The authors suggest that this uptake is facilitated by increased macropinocytosis. iExosomes are able to reduce KRAS oncogenic signalling and reduce tumour growth in mouse models of pancreatic cancer.