Coupling photodynamic hypoxia amplification with a self-reporting chemiluminescent prodrug for adaptive precision therapy

Hypoxia is a hallmark of solid tumors that provides a therapeutic window for hypoxia-activated prodrugs (HAPs). However, the therapeutic performance of HAPs is often limited by heterogeneous tumor hypoxia and the lack of real-time feedback on prodrug activation. Herein, we report a self-reporting nanomedicine, CL-Azo-CPT/Ce6 NPs, that integrates hypoxia amplification with chemiluminescent monitoring in a “Sense-Amplify-Report” strategy. The system combines a photosensitizer, chlorin e6 (Ce6), with a hypoxia-responsive chemiluminescent prodrug, CL-Azo-CPT, in which camptothecin (CPT) is linked to a Schaap's dioxetane scaffold through an azobenzene (azo) trigger. Upon irradiation, Ce6-mediated photodynamic therapy consumes local oxygen and aggravates tumor hypoxia, thereby promoting azoreductase-mediated azo cleavage and accelerating CPT release. This activation process is accompanied by chemiluminescence emission, the intensity of which shows a stoichiometric correlation with drug release and thus provides an excitation-free, real-time readout of prodrug activation. In vitro studies and evaluation in a murine peritoneal metastasis model demonstrated enhanced antitumor efficacy, marked tumor regression, and prolonged survival. This work establishes a hypoxia-amplified and self-reporting chemo-photodynamic platform that addresses two central limitations of HAPs, namely insufficient activation and the absence of in vivo activation feedback.