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Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer

Author

Listed:
  • Chi-Ling Chiang

    (The Ohio State University
    The Ohio State University)

  • Yifan Ma

    (The Ohio State University
    The Ohio State University)

  • Ya-Chin Hou

    (National Cheng Kung University
    National Cheng Kung University Hospital, College of Medicine, 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
    East China University of Science and Technology)

  • Hsiao-Chun Liu

    (National Cheng Kung University
    National Cheng Kung University Hospital, College of Medicine, 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
    National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University)

  • Andrew S. Lee

    (Shenzhen Bay Laboratory
    Peking University Shenzhen Graduate School)

  • L. James Lee

    (The Ohio State University
    National Yang Ming Chiao Tung University
    Spot Biosystems Ltd.)

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.

Suggested Citation

  • 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 Le, 2023. "Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42402-3
    DOI: 10.1038/s41467-023-42402-3
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    References listed on IDEAS

    as
    1. Ryosuke Kojima & Daniel Bojar & Giorgio Rizzi & Ghislaine Charpin-El Hamri & Marie Daoud El-Baba & Pratik Saxena & Simon Ausländer & Kelly R. Tan & Martin Fussenegger, 2018. "Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Emeline Bonsergent & Eleonora Grisard & Julian Buchrieser & Olivier Schwartz & Clotilde Théry & Grégory Lavieu, 2021. "Quantitative characterization of extracellular vesicle uptake and content delivery within mammalian cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Sushrut Kamerkar & Valerie S. LeBleu & Hikaru Sugimoto & Sujuan Yang & Carolina F. Ruivo & Sonia A. Melo & J. Jack Lee & Raghu Kalluri, 2017. "Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer," Nature, Nature, vol. 546(7659), pages 498-503, June.
    4. Jiaming Hu & Yan Sheng & Kwang Joo Kwak & Junfeng Shi & Bohao Yu & L. James Lee, 2017. "A signal-amplifiable biochip quantifies extracellular vesicle-associated RNAs for early cancer detection," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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