Redox-programmed theranostic system with instant Response: Light-Triggered methylene blue activation driving self-amplified PDT through glutathione depletion and synergistic chemotherapy

Photodynamic therapy (PDT) has emerged as an attractive therapeutic modality owing to its non-invasiveness and precise spatiotemporal controllability. However, the inherent limitations of monotherapy and the tumor recognition properties of conventional photosensitizers have significantly limited their therapeutic efficacy. In this study we developed Sanger-MB-HCPT, a photoactivatable theranostic prodrug integrating methylene blue (MB) and hydroxycamptothecin (HCPT) through rational molecular engineering. The system features: 1) photocleavable FDNP group enabling fluorescence recovery and precise MB activation under 660 nm irradiation, addressing metabolic instability in conventional photosensitizers; 2) disulfide linkages mediating tumor-selective HCPT release through glutathione (GSH) responsiveness. Notably, GSH consumption during drug liberation concurrently attenuates ROS scavenging, establishing a self-amplifying mechanism for enhanced PDT efficacy. This dual-activation strategy achieves spatiotemporally controlled ROS generation and chemotherapy, with in vivo studies demonstrating 89.7 % tumor suppression through synergistic effects. This integrated approach establishes a novel therapeutic strategy for precision oncology, effectively overcoming current limitations in conventional PDT while enabling real-time treatment visualization.