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.