Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

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 () and Haijun Yu ()
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Jing Gao: Tongji University
Bo Hou: Chinese Academy of Sciences
Qiwen Zhu: Chinese Academy of Sciences
Lei Yang: Nanjing University of Chinese Medicine
Xingyu Jiang: Nanjing University of Chinese Medicine
Zhifeng Zou: Chinese Academy of Sciences
Xutong Li: Chinese Academy of Sciences
Tianfeng Xu: Chinese Academy of Sciences
Mingyue Zheng: Chinese Academy of Sciences
Yi-Hung Chen: Wuhan University
Zhiai Xu: East China Normal University
Huixiong Xu: Fudan University
Haijun Yu: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Date: 2022
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DOI: 10.1038/s41467-022-32050-4

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