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

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

机构地区：[1]College of Physics and Chemistry,Hunan First Normal University,Changsha 410205,China [2]Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine,College of Biomedical Sciences,College of Chemistry and Chemical Engineering,Hunan University,Changsha 410082,China [3]Xiangtan Central Hospital,Xiangtan 411199,China

出　　处：《Science China Chemistry》2025年第2期687-693,共7页中国科学(化学英文版)

基　　金：supported by the National Natural Science Foundation of China(NSFC)Programs(22204046);the Hunan Science Fund for Excellent Young Scholars(2023JJ20002);the National Key Research Program(2019YFA0905800);the Changsha Municipal Natural Science Foundation(kq2402088);the Scientific Research Fund of Hunan Provincial Education Department(22B0874,23B0844).

摘　　要：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 framework90(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.

关 键 词：inducible proteolysis DNAZYME transcription factor ZIF-90 NF-ΚB 

分 类 号：R73[医药卫生—肿瘤]