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Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem

Author

Listed:
  • Xuexiang Han

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences
    Tsinghua University)

  • Yiye Li

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Ying Xu

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Xiao Zhao

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Yinlong Zhang

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Xiao Yang

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Yongwei Wang

    (Chinese Academy of Sciences)

  • Ruifang Zhao

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Gregory J. Anderson

    (Royal Brisbane Hospital)

  • Yuliang Zhao

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

  • Guangjun Nie

    (National Center for Nanoscience and Technology
    University of Chinese Academy of Sciences)

Abstract

Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.

Suggested Citation

  • Xuexiang Han & Yiye Li & Ying Xu & Xiao Zhao & Yinlong Zhang & Xiao Yang & Yongwei Wang & Ruifang Zhao & Gregory J. Anderson & Yuliang Zhao & Guangjun Nie, 2018. "Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05906-x
    DOI: 10.1038/s41467-018-05906-x
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    Cited by:

    1. Zi-Yi Han & Zhuang-Jiong Fu & Yu-Zhang Wang & Cheng Zhang & Qi-Wen Chen & Jia-Xin An & Xian-Zheng Zhang, 2024. "Probiotics functionalized with a gallium-polyphenol network modulate the intratumor microbiota and promote anti-tumor immune responses in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Xuexiang Han & Ningqiang Gong & Lulu Xue & Margaret M. Billingsley & Rakan El-Mayta & Sarah J. Shepherd & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2023. "Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Jingchao Li & Yu Luo & Ziling Zeng & Dong Cui & Jiaguo Huang & Chenjie Xu & Liping Li & Kanyi Pu & Ruiping Zhang, 2022. "Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Xin Li & Tuying Yong & Zhaohan Wei & Nana Bie & Xiaoqiong Zhang & Guiting Zhan & Jianye Li & Jiaqi Qin & Jingjing Yu & Bixiang Zhang & Lu Gan & Xiangliang Yang, 2022. "Reversing insufficient photothermal therapy-induced tumor relapse and metastasis by regulating cancer-associated fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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