ZIF-90-loaded DNAzyme-responsive PROTAC for the self-powered degradation of NF-κB

IF 10.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Science China Chemistry Pub Date : 2024-10-21 DOI:10.1007/s11426-024-2246-0

Min Hou, Liang Sun, Tianyu Ren, Mingda Li, Chao Hu, Rong Liu, Shuang Gu, Mingyan Jiang, Jian-Hui Jiang, Jianjun He

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引用次数: 0

Abstract

Transcription factors (TFs) play vital roles in regulating gene expressions. Dysregulated or mutated TFs are implicated in a wide array of diseases, highlighting their potential as drug targets. However, TFs are considered undruggable by conventional inhibitor-based modalities. The recently emerged proteolysis targeting chimeras (PROTACs) have exhibited great potential in tackling TFs. In particular, DNA-ligand chimeras that arm E3 ligase-recruiting ligands to TF-binding double-strand DNA represent a promising strategy for the targeted proteolysis of TFs. Here, we report a DNAzyme-inducible PROTAC (DzTAC) that selectively degrades NF-κB in a zinc ion-dependent manner. We further applied zinc-imidazolate metal-organic framework-90 (ZIF-90) to encapsulate DzTAC (ZIF-90@DzTAC), facilitating its delivery into cancer cells while self-supplying Zn²⁺ via adenosine triphosphate (ATP)-triggered ZIF-90 dissociation. Moreover, ZIF-90@DzTAC can enhance the treatment efficacy of doxorubicin-based chemotherapy in tumor-bearing mice. The developed DzTAC provides specific modulation over TF activity and opens an avenue for more functional nucleic acid-based control over targeted protein degradation.

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来源期刊

Science China Chemistry CHEMISTRY, MULTIDISCIPLINARY-

CiteScore

14.40

自引率

7.30%

发文量

3787

审稿时长

2.2 months

期刊介绍： Science China Chemistry, co-sponsored by the Chinese Academy of Sciences and the National Natural Science Foundation of China and published by Science China Press, publishes high-quality original research in both basic and applied chemistry. Indexed by Science Citation Index, it is a premier academic journal in the field. Categories of articles include: Highlights. Brief summaries and scholarly comments on recent research achievements in any field of chemistry. Perspectives. Concise reports on thelatest chemistry trends of interest to scientists worldwide, including discussions of research breakthroughs and interpretations of important science and funding policies. Reviews. In-depth summaries of representative results and achievements of the past 5–10 years in selected topics based on or closely related to the research expertise of the authors, providing a thorough assessment of the significance, current status, and future research directions of the field.