Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy
Weishan Wang, Chenghong Zhu, Bin Zhang, Yi Feng, Yan Zhang, Jinbo Li
Abstract
Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging to precisely control PROTAC function in tumor regions in vivo . We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis in tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate of PROTAC linked with an NIR photosensitizer through a singlet oxygen ( 1 O 2 )-cleavable linker. The activity of PROTAC is initially silenced but can be remotely switched on upon NIR photoirradiation to generate 1 O 2 by the photosensitizer. We demonstrated that NAP enabled tumor-specific degradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructed manner. This in combination with photodynamic therapy (PDT) elicited an effective suppression of tumor growth. This work thus presents a novel approach for spatiotemporal control over targeted protein degradation by PROTAC.