Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy

Confining the protein degradation activity of proteolysis-targetingchimera (PROTAC) to cancer lesions ensures precision treatment. However,it still remains challenging to precisely control PROTAC functionin tumor regions in vivo. We herein describe a near-infrared(NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysisin tumor-bearing mice. NAP is formed by molecular self-assembly froman amphiphilic conjugate of PROTAC linked with an NIR photosensitizerthrough a singlet oxygen (O-1(2))-cleavable linker.The activity of PROTAC is initially silenced but can be remotely switchedon upon NIR photoirradiation to generate O-1(2) by the photosensitizer. We demonstrated that NAP enabled tumor-specificdegradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructedmanner. This in combination with photodynamic therapy (PDT) elicitedan effective suppression of tumor growth. This work thus presentsa novel approach for spatiotemporal control over targeted proteindegradation by PROTAC.

Automated summary

Researchers have developed a near-infrared photoactivatable nano-PROTAC (NAP) that enables remote control of protein degradation in tumors. NAP, formed by molecular self-assembly, can be activated by NIR photoirradiation to selectively degrade proteins in tumor regions.