Yao Qingxin, Wu Ziyang, Li Jiaan, Hu Xiaoqian, Xu Hanlin, Jiang Xingyu, Gao Yuan
State Key Laboratory of Chemical Resource Engineering, MOE Key Lab of Biomedical Materials of Natural Macromolecules, Beijing University of Chemical Technology, Beijing 100029, China.
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
J Am Chem Soc. 2025 May 28;147(21):18208-18218. doi: 10.1021/jacs.5c04857. Epub 2025 May 15.
Proteolysis-Targeting Chimeras (PROTACs) represent a transformative therapeutic platform for targeted protein degradation across diverse disease indications. However, their potent catalytic activity in normal tissues raises significant concerns regarding off-target toxicity. Here, we present a novel supramolecular self-assembly platform for the bioorthogonal control of PROTAC prodrug activation, enabling tumor-specific protein degradation with minimized systemic toxicity. By exploiting the overproduction of reactive oxygen species (ROS) in pancreatic cancer cells, the supramolecular self-assembly approach selectively accumulates bioorthogonal reaction triggers within the targeted malignant cells, which subsequently facilitates the spatiotemporally controlled activation of the bioorthogonally caged PROTAC. This tumor-selective activation mechanism demonstrates enhanced degradation efficiency in pancreatic cancer cells compared to normal cells. In vivo studies reveal potent tumor growth inhibition with complete preservation of major organ histology, confirming the therapeutic index enhancement achieved through a controllable activation strategy. This biomimetic activation platform establishes a generalizable framework for safer PROTAC-based therapies by integrating tumor-specific microenvironmental cues with bioorthogonal reaction engineering.
蛋白酶靶向嵌合体（PROTACs）是一种变革性的治疗平台，可针对多种疾病适应症实现靶向蛋白降解。然而，它们在正常组织中的强大催化活性引发了对脱靶毒性的重大担忧。在此，我们提出了一种新型超分子自组装平台，用于对PROTAC前药激活进行生物正交控制，从而在将全身毒性降至最低的情况下实现肿瘤特异性蛋白降解。通过利用胰腺癌细胞中活性氧（ROS）的过量产生，超分子自组装方法在靶向恶性细胞内选择性积累生物正交反应触发剂，随后促进生物正交笼蔽PROTAC的时空控制激活。与正常细胞相比，这种肿瘤选择性激活机制在胰腺癌细胞中显示出更高的降解效率。体内研究表明，该方法能有效抑制肿瘤生长，同时主要器官组织学完全保留，证实了通过可控激活策略实现了治疗指数的提高。这个仿生激活平台通过将肿瘤特异性微环境线索与生物正交反应工程相结合，为更安全的基于PROTAC的治疗建立了一个可推广的框架。
