Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer

Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y. S. Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F. Huang (), Yan-Shen Shan (), Andrew S. Lee () and L. James Lee ()
Additional contact information
Chi-Ling Chiang: The Ohio State University
Yifan Ma: The Ohio State University
Ya-Chin Hou: National Cheng Kung University
Junjie Pan: The Ohio State University
Sin-Yu Chen: National Yang Ming Chiao Tung University
Ming-Hsien Chien: Academia Sinica
Zhi-Xuan Zhang: National Yang Ming Chiao Tung University
Wei-Hsiang Hsu: National Yang Ming Chiao Tung University
Xinyu Wang: The Ohio State University
Jingjing Zhang: The Ohio State University
Hong Li: The Ohio State University
Lili Sun: East China University of Science and Technology
Shannon Fallen: Institute of Systems Biology
Inyoul Lee: Institute of Systems Biology
Xing-Yu Chen: National Yang Ming Chiao Tung University
Yeh-Shiu Chu: National Yang Ming Chiao Tung University
Chi Zhang: The Ohio State University
Tai-Shan Cheng: National Yang Ming Chiao Tung University
Wen Jiang: The University of Texas MD Anderson Cancer Center
Betty Y. S. Kim: The University of Texas MD Anderson Cancer Center
Eduardo Reategui: The Ohio State University
Robert Lee: The Ohio State University
Yuan Yuan: The Ohio State University
Hsiao-Chun Liu: National Cheng Kung University
Kai Wang: Institute of Systems Biology
Michael Hsiao: Academia Sinica
Chi-Ying F. Huang: National Yang Ming Chiao Tung University
Yan-Shen Shan: National Cheng Kung University
Andrew S. Lee: Shenzhen Bay Laboratory
L. James Lee: The Ohio State University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42402-3

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