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Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy

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  • Chi Zhang

    (Nanyang Technological University)

  • Ziling Zeng

    (Nanyang Technological University)

  • Dong Cui

    (Nanyang Technological University)

  • Shasha He

    (Nanyang Technological University)

  • Yuyan Jiang

    (Nanyang Technological University)

  • Jingchao Li

    (Nanyang Technological University)

  • Jiaguo Huang

    (Nanyang Technological University)

  • Kanyi Pu

    (Nanyang Technological University
    Nanyang Technological University)

Abstract

Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPNpro) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPNpro can remotely generate singlet oxygen (1O2) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPNpro is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.

Suggested Citation

  • Chi Zhang & Ziling Zeng & Dong Cui & Shasha He & Yuyan Jiang & Jingchao Li & Jiaguo Huang & Kanyi Pu, 2021. "Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23194-w
    DOI: 10.1038/s41467-021-23194-w
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    Cited by:

    1. Bo Wang & Jing Chen & Julia S. Caserto & Xi Wang & Minglin Ma, 2022. "An in situ hydrogel-mediated chemo-immunometabolic cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Tingting Cui & Yu Zhang & Geng Qin & Yue Wei & Jie Yang & Ying Huang & Jinsong Ren & Xiaogang Qu, 2023. "A neutrophil mimicking metal-porphyrin-based nanodevice loaded with porcine pancreatic elastase for cancer therapy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Xiaoying Kang & Yuan Zhang & Jianwen Song & Lu Wang & Wen Li & Ji Qi & Ben Zhong Tang, 2023. "A photo-triggered self-accelerated nanoplatform for multifunctional image-guided combination cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Zhaoting Li & Fanyi Mo & Yixin Wang & Wen Li & Yu Chen & Jun Liu & Ting-Jing Chen-Mayfield & Quanyin Hu, 2022. "Enhancing Gasdermin-induced tumor pyroptosis through preventing ESCRT-dependent cell membrane repair augments antitumor immune response," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Chi Zhang & Jingsheng Huang & Ziling Zeng & Shasha He & Penghui Cheng & Jingchao Li & Kanyi Pu, 2022. "Catalytical nano-immunocomplexes for remote-controlled sono-metabolic checkpoint trimodal cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Yang Yang & Jinshu Huang & Wei Wei & Qin Zeng & Xipeng Li & Da Xing & Bo Zhou & Tao Zhang, 2022. "Switching the NIR upconversion of nanoparticles for the orthogonal activation of photoacoustic imaging and phototherapy," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Mengxue Zhou & Jiaxin Wang & Jiaxing Pan & Hui Wang & Lujia Huang & Bo Hou & Yi Lai & Fengyang Wang & Qingxiang Guan & Feng Wang & Zhiai Xu & Haijun Yu, 2023. "Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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