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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer
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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer
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Journal Article
Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer
2023
Overview
Pancreatic ductal adenocarcinoma (PDAC) tumours 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 target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours 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 release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.
KRAS
G12D
mutations frequently co-occur with mutated TP53 tumour suppressor in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors report the design of dual targeted therapeutic extracellular vesicles containing high copy numbers of TP53 mRNA and siKRAS
G12D
, showing anti-tumor activity in PDAC preclinical models.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/107
/ 13/89
/ 42/109
/ 42/41
/ 631/61
/ 82/80
/ Animals
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - metabolism
/ Carcinoma, Pancreatic Ductal - therapy
/ Deoxycytidine - therapeutic use
/ Extracellular Vesicles - metabolism
/ Humanities and Social Sciences
/ Humans
/ Mice
/ mRNA
/ Mutation
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Pancreatic Neoplasms - therapy
/ Proteins
/ RNA
/ Science
/ Tumors
/ Vesicles
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