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

Chi Zhang, Ziling Zeng, Dong Cui, Shasha He, Yuyan Jiang, Jingchao Li, Jiaguo Huang and Kanyi Pu ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23194-w

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