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.