Dual targeted extracellular vesicles regulating oncogenic genes in pancreatic cancer [Human Array]

Pancreatic ductal adenocarcinoma (PDAC) tumors carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to high solid tumor burden like PDAC. Here, we report a dual-targeted extracellular vesicle (EV) carrying high loads of RNA that effectively suppresses large PDAC tumors in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation released abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dual-targeted EVs effectively suppressed large orthotopic PANC-1 and patient derived xenograft tumors in mice and extended animal survival. This work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumors. HUMAN_arrays