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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer

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, Wen, Kim, Betty Y. S., Reategui, Eduardo, Lee, Robert, Yuan, Yuan, Liu, Hsiao-Chun, Wang, Kai, Hsiao, Michael, Huang, Chi-Ying F., Shan, Yan-Shen, Lee, Andrew S., James Lee, L.·2023·Nature Communications
DOI 10.1038/s41467-023-42402-3PMC PMC10593751
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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.

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Metadata

Authors
Chiang, C.-L., Ma, Y., Hou, Y.-C., Pan, J., Chen, S.-Y., Chien, M.-H., Zhang, Z.-X., Hsu, W.-H., Wang, X., Zhang, J., Li, H., Sun, L., Fallen, S., Lee, I., Chen, X.-Y., Chu, Y.-S., Zhang, C., Cheng, T.-S., Jiang, W., Kim, B. Y. S., Reategui, E., Lee, R., Yuan, Y., Liu, H.-C., Wang, K., Hsiao, M., Huang, C.-Y. F., Shan, Y.-S., Lee, A. S., & James Lee, L.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-23
Volume
14
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-023-42402-3
PMC
PMC10593751
Cited by
63
References
11
Language
en
Licence
Funders
National Science and Technology Council

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