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 researchers from University of Texas MD Anderson Cancer Center 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. These results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.
iExosomes suppress pancreatic cancer progression in KTC and KPC genetically engineered mouse models
a, Kaplan–Meier survival curve of KTC (early treatment) mice. n = 8 mice (siKrasG12D iExo); n = 6 mice (control Exo). b, Kaplan–Meier survival curve of KTC mice. n = 7 mice (siKrasG12D iExo, control Exo); n = 5 mice (shKrasG12D iExo). c, Tumour burden (early treatment) at the experimental end point. n = 8 mice (siKrasG12D iExo); n = 6 mice (control Exo). d, Tumour burden at 44 days of age. n = 3 mice per group. e, H&E-stained tumours from 44-day-old KTC mice and relative percentages in histological phenotypes. PanIN, pancreatic intraepithelial neoplasia. n = 3 mice per group. f, Masson’s trichrome staining (MTS), TUNEL, Ki-67, and p-ERK and CK19 immunolabelling of 44-day-old KTC mice. n = 3 mice per group. g, KrasG12D transcript levels in tumours of age-matched (44-day-old) KTC mice. n = 3 mice per group. h, Tumour volume at baseline (determined by magnetic resonance imaging; MRI). n = 6 mice per group. i, Kaplan–Meier curve of KPC mice. n = 6 mice per group. Scale bars, 100 μm and 50 μm (e, inset). Data are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, log-rank Mantel–Cox test (a, b, i) and unpaired two-tailed t-test (c–h). See accompanying Source Data.