Modularized GSH‐Proton Tandem‐Responsive “Off‐Brighter” Persistent Luminescent Nano‐System for Visualized Synergetic PTT & CDT of Mastocarcinoma

Visualized theranostics is a powerful tool for guiding cancer diagnosis, therapy, and prognosis through medical imaging; nevertheless, simultaneously achieving high imaging contrast, reliable therapeutic efficacy, inter-component cooperativity, and broad methodological versatility with a facile strategy remains exceedingly challenging. For the first time, this study introduces a novel modular "Off-Brighter" persistent luminescence (PersL) theranostic strategy for visualized cancer therapy. The nano-agent integrates two functional modules: a proton-responsive PersL imaging brick (ZR) optimized via dye-sensitization, and a GSH-responsive synergistic photothermal/chemodynamic therapy brick (PAHIR-Fcss) loaded with IR808 and FcSH. FcSH temporarily quenches ZR's PersL, creating "GSH-proton" tandem-responsive "Off-Brighter" activation that enhances luminescence 12.3-fold and achieves tumor imaging contrast of 274.95. Real-time imaging guided drug delivery monitoring, identifying the 3rd h post-injection as optimal for combination therapy. The synergistic photothermal/chemodynamic approach attained 96.2% tumor suppression in murine breast cancer models. Subsequent PersL imaging-based assessment determined that a single 14-day treatment course optimizes efficacy while preventing overtreatment risks. The modular design enables free exchange of imaging and therapeutic components, offering a versatile, generalizable platform for tailored clinical applications.