An Azoreductase-Activated Self-monitoring Prodrug for Chemiluminescence Imaging and Safe Chemotherapy Breast Cancer

Theranostic prodrugs predominantly rely on fluorogenic responses to convey diagnostic signals during chemotherapeutic activation. While chemiluminescence (<b>CL</b>) detection offers superior signal-to-noise ratios over fluorescence, the utilization of Schaap's as a module in diagnostic prodrugs remains underexplored, limiting advancements in this field. Herein, we present the first Azoreductase (<b>AZR</b>)-activated self-reporting theranostic prodrug utilizing a <b>CL</b> feedback mechanism. This prodrug has azo (-N = N-) bonds, which can serve as an <b>AZR</b> recognition site and link the melphalan analogue and Schaap's scaffold. Under hypoxic tumor conditions, <b>AZR</b>-mediated reduction of azobenzene triggers prodrug cleavage, releasing the active drug and <b>CL</b> signal. The <b>AZR</b>-selective activation can facilitate tumor-specific therapeutic effects, thus enabling precision chemotherapy. Our study has confirmed that Schaap's <b>CL</b> platform, activated by <b>AZR</b>, is a promising strategy for integrating real-time diagnostic imaging with controllable treatment. These findings advance the development of <b>CL</b>-based theranostic agents for safe and effective breast cancer treatment.