Tandem‐Activatable PROTAC Prodrug for Tumor Biomarker‐Driven Near‐Infrared Opto‐Proteolysis

Tumor‐specific protein degradation is crucial for successful cancer treatment by proteolysis‐targeting chimera (PROTAC), which however still remains challenging. Here, we report a tandem‐activatable PROTAC prodrug (TAP) strategy for precise on‐tumor proteolysis in vivo. TAP is constructed by caging PROTAC with a tumor‐homing cyclopeptide through a tandem‐locking linker, which comprises a singlet‐oxygen (1O2) cleavable moiety, a near‐infrared (NIR) photosensitizer (PS) and a Cathepsin B (CatB)‐cleavable dipeptide substrate. The proteolytic activity of TAP is initially turned off but can be sequentially switched on by tumor biomarker enzyme CatB and NIR light. Such a tandem‐lock design ensures that PROTAC exclusively degrade oncoprotein target in tumor. The results revealed that TAP carried out a tumor‐selective degradation of bromodomain‐containing protein 4 (BRD4) under the cooperative action by CatB and NIR light, which further synergized with photodynamic therapy (PDT) by the PS to suppress tumor growth. This work thus presents the first tandem‐activatable approach for spatiotemporally controlled proteolysis to minimize the off‐tumor toxicity of PROTAC.