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Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome chemo-immune-resistance

Author

Listed:
  • Haozhe Huang

    (University of Pittsburgh
    University of Pittsburgh)

  • Yiqing Mu

    (University of Pittsburgh
    University of Pittsburgh)

  • Yixian Huang

    (University of Pittsburgh
    University of Pittsburgh)

  • Beihong Ji

    (University of Pittsburgh)

  • Yifei Wang

    (University of Pittsburgh
    University of Pittsburgh)

  • Chien-Yu Chen

    (University of Pittsburgh
    University of Pittsburgh)

  • Yuang Chen

    (University of Pittsburgh
    University of Pittsburgh)

  • Zhangyi Luo

    (University of Pittsburgh
    University of Pittsburgh)

  • Sihan Li

    (University of Pittsburgh
    University of Pittsburgh)

  • Ziqian Zhang

    (University of Pittsburgh
    University of Pittsburgh)

  • Luxuan Wang

    (University of Pittsburgh)

  • James F. Conway

    (University of Pittsburgh)

  • Da Yang

    (University of Pittsburgh
    University of Pittsburgh)

  • Junmei Wang

    (University of Pittsburgh)

  • Jingjing Sun

    (University of Pittsburgh
    University of Pittsburgh)

  • Song Li

    (University of Pittsburgh
    University of Pittsburgh)

Abstract

SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy.

Suggested Citation

  • Haozhe Huang & Yiqing Mu & Yixian Huang & Beihong Ji & Yifei Wang & Chien-Yu Chen & Yuang Chen & Zhangyi Luo & Sihan Li & Ziqian Zhang & Luxuan Wang & James F. Conway & Da Yang & Junmei Wang & Jingjin, 2025. "Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome chemo-immune-resistance," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59490-y
    DOI: 10.1038/s41467-025-59490-y
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    References listed on IDEAS

    as
    1. Yichao Chen & Rui Xia & Yixian Huang & Wenchen Zhao & Jiang Li & Xiaolan Zhang & Pengcheng Wang & Raman Venkataramanan & Jie Fan & Wen Xie & Xiaochao Ma & Binfeng Lu & Song Li, 2016. "An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    2. Nitin Roper & Moises J. Velez & Alberto Chiappori & Yoo Sun Kim & Jun S. Wei & Sivasish Sindiri & Nobuyuki Takahashi & Deborah Mulford & Suresh Kumar & Kris Ylaya & Christopher Trindade & Irena Manuky, 2021. "Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Xin Li & Yong Hu & Xingcai Zhang & Xiangyang Shi & Wolfgang J. Parak & Andrij Pich, 2024. "Transvascular transport of nanocarriers for tumor delivery," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Zhangyi Luo & Yixian Huang & Neelu Batra & Yuang Chen & Haozhe Huang & Yifei Wang & Ziqian Zhang & Shichen Li & Chien-Yu Chen & Zehua Wang & Jingjing Sun & Qiming Jane Wang & Da Yang & Binfeng Lu & Ja, 2024. "Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
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