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; L. James Lee

doi:10.1038/s41467-023-42402-3

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. KimEduardo Reategui, Robert Lee, Yuan Yuan, Hsiao Chun Liu, Kai Wang, Michael Hsiao, Chi Ying F. Huang, Yan Shen Shan, Andrew S. Lee, L. James Lee

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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.

Original language	English (US)
Article number	6692
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42402-3
State	Published - Dec 2023

ASJC Scopus subject areas

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

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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., ... James Lee, L. (2023). Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer. Nature communications, 14(1), Article 6692. https://doi.org/10.1038/s41467-023-42402-3

Chiang, CL, Ma, Y, Hou, YC, Pan, J, Chen, SY, Chien, MH, Zhang, ZX, Hsu, WH, Wang, X, Zhang, J, Li, H, Sun, L, Fallen, S, Lee, I, Chen, XY, Chu, YS, Zhang, C, Cheng, TS, Jiang, W , Kim, BYS, Reategui, E, Lee, R, Yuan, Y, Liu, HC, Wang, K, Hsiao, M, Huang, CYF, Shan, YS, Lee, AS & James Lee, L 2023, 'Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer', Nature communications, vol. 14, no. 1, 6692. https://doi.org/10.1038/s41467-023-42402-3

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title = "Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer",

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{\textregistered}-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.",

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

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doi = "10.1038/s41467-023-42402-3",

language = "English (US)",

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AU - Chiang, Chi Ling

AU - Ma, Yifan

AU - Hou, Ya Chin

AU - Pan, Junjie

AU - Chen, Sin Yu

AU - Chien, Ming Hsien

AU - Zhang, Zhi Xuan

AU - Hsu, Wei Hsiang

AU - Wang, Xinyu

AU - Zhang, Jingjing

AU - Li, Hong

AU - Sun, Lili

AU - Fallen, Shannon

AU - Lee, Inyoul

AU - Chen, Xing Yu

AU - Chu, Yeh Shiu

AU - Zhang, Chi

AU - Cheng, Tai Shan

AU - Jiang, Wen

AU - Kim, Betty Y.S.

AU - Reategui, Eduardo

AU - Lee, Robert

AU - Yuan, Yuan

AU - Liu, Hsiao Chun

AU - Wang, Kai

AU - Hsiao, Michael

AU - Huang, Chi Ying F.

AU - Shan, Yan Shen

AU - Lee, Andrew S.

AU - James Lee, L.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer

Abstract

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