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

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 () and Zhiai Xu ()
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Jing Gao: Chinese Academy of Sciences
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
Huixiong Xu: Fudan University
Zhiai Xu: East China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50735-w

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