Near‐Infrared Light‐Activated Transcription Factor‐Targeted Proteolysis‐Targeting Chimeras Nanomachine for Targeted Degradation of Transcription Factors

Transcription factors (TFs) are important gene regulators whose abnormal expression or function is involved in the occurrence of various diseases. The emergence of transcription factor-targeted proteolysis-targeting chimeras (TF-PROTACs) using DNA with a specific sequence as the targeting ligand of TFs provides a promising strategy to overcome the difficulties of using small molecules to inhibit TFs without well-defined ligand-binding pockets. A smart nanomachine is reported to realize near-infrared (NIR) light-triggered release and activation of TF-PROTAC using upconversion nanoparticles loaded with caged TF-PROTAC targeting the transcriptional factor NF-κB. The release of the active TF degrader (dNF-κB) under 980 nm NIR irradiation is demonstrated in a controlled manner, enabling precise control of the degradation of the transcriptional factor NF-κB p65 in live cells. The construction of the NIR-responsive nanomachine makes it possible to load and release various TF-PROTACs to degrade different transcriptional factors on demand with spatial and temporal resolution.