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A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy

Author

Listed:
  • Jing Gao

    (Chinese Academy of Sciences
    Fudan University
    Tongji University)

  • Xingyu Jiang

    (East China Normal University)

  • Shumin Lei

    (Nanjing University of Chinese Medicine)

  • Wenhao Cheng

    (Chinese Academy of Sciences)

  • Yi Lai

    (Chinese Academy of Sciences)

  • Min Li

    (Chinese Academy of Sciences)

  • Lei Yang

    (Chinese Academy of Sciences)

  • Peifeng Liu

    (Shanghai Jiao Tong University)

  • Xiao-hua Chen

    (Chinese Academy of Sciences)

  • Min Huang

    (Chinese Academy of Sciences)

  • Haijun Yu

    (Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

  • Huixiong Xu

    (Fudan University)

  • Zhiai Xu

    (East China Normal University)

Abstract

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.

Suggested Citation

  • Jing Gao & Xingyu Jiang & Shumin Lei & Wenhao Cheng & Yi Lai & Min Li & Lei Yang & Peifeng Liu & Xiao-hua Chen & Min Huang & Haijun Yu & Huixiong Xu & Zhiai Xu, 2024. "A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50735-w
    DOI: 10.1038/s41467-024-50735-w
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    References listed on IDEAS

    as
    1. Corbin E. Meacham & Sean J. Morrison, 2013. "Tumour heterogeneity and cancer cell plasticity," Nature, Nature, vol. 501(7467), pages 328-337, September.
    2. Jing Gao & Bo Hou & Qiwen Zhu & Lei Yang & Xingyu Jiang & Zhifeng Zou & Xutong Li & Tianfeng Xu & Mingyue Zheng & Yi-Hung Chen & Zhiai Xu & Huixiong Xu & Haijun Yu, 2022. "Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Jiaqiang Dong & Jiong Li & Yang Li & Zhikun Ma & Yongxin Yu & Cun-Yu Wang, 2021. "Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Tannishtha Reya & Sean J. Morrison & Michael F. Clarke & Irving L. Weissman, 2001. "Stem cells, cancer, and cancer stem cells," Nature, Nature, vol. 414(6859), pages 105-111, November.
    5. Jing Gao & Bo Hou & Qiwen Zhu & Lei Yang & Xingyu Jiang & Zhifeng Zou & Xutong Li & Tianfeng Xu & Mingyue Zheng & Yi-Hung Chen & Zhiai Xu & Huixiong Xu & Haijun Yu, 2022. "Author Correction: Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
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