Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer

Author:

Chiang Chi-Ling,Ma Yifan,Hou Ya-Chin,Pan Junjie,Chen Sin-Yu,Chien Ming-Hsien,Zhang Zhi-Xuan,Hsu Wei-Hsiang,Wang Xinyu,Zhang Jingjing,Li Hong,Sun Lili,Fallen Shannon,Lee Inyoul,Chen Xing-Yu,Chu Yeh-Shiu,Zhang Chi,Cheng Tai-Shan,Jiang WenORCID,Kim Betty Y. S.ORCID,Reategui Eduardo,Lee Robert,Yuan Yuan,Liu Hsiao-Chun,Wang Kai,Hsiao MichaelORCID,Huang Chi-Ying F.ORCID,Shan Yan-ShenORCID,Lee Andrew S.ORCID,James Lee L.ORCID

Abstract

AbstractPancreatic 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.

Funder

National Science and Technology Council

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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