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

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.