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 ( CL ) 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 ( AZR )-activated self-reporting theranostic prodrug utilizing a CL feedback mechanism. This prodrug has azo (-N = N-) bonds, which can serve as an AZR recognition site and link the melphalan analogue and Schaap’s scaffold. Under hypoxic tumor conditions, AZR -mediated reduction of azobenzene triggers prodrug cleavage, releasing the active drug and CL signal. The AZR -selective activation can facilitate tumor-specific therapeutic effects, thus enabling precision chemotherapy. Our study has confirmed that Schaap’s CL platform, activated by AZR, is a promising strategy for integrating real-time diagnostic imaging with controllable treatment. These findings advance the development of CL -based theranostic agents for safe and effective breast cancer treatment.