A dual-modal GSH depletion and NIR-triggered nanoplatform for cascade-amplified phototherapy

In tumor phototherapy, the intracellular antioxidant defenses, such as high concentrations of glutathione (GSH) and inefficient generation of reactive oxygen species (ROS) significantly restrict the therapeutic efficacy. In this research, we construct a dual-modal GSH depletion and near-infrared (NIR)-triggered nanoplatform (Ce6@CDP) for cascade-amplified photothermal therapy (PTT) and photodynamic therapy (PDT). This nanoplatform featured a hollow mesoporous copper sulfide (CuS) core loaded with Ce6 and encapsulated by a disulfide bond-containing polymer (DS-ANPA-PEG). Upon tumor accumulation, the polymer DS-ANPA-PEG reacts with intracellular GSH to form highly reactive quinone methides (QMs), enabling rapid GSH depletion through alkylation. This dual GSH depletion ‌intensifies oxidative stress, potentiating Ce6-based PDT efficacy. Additionally, the CuS carrier exhibits high photothermal conversion performance (η = 39.68 %), enabling‌ PTT under 808 nm laser irradiation ‌for‌ synergistic tumor eradication. Both in vitro and in vivo studies ‌demonstrate that the PDT/PTT combination therapy ‌significantly‌ inhibits tumor growth while maintaining‌ negligible systemic toxicity. Our findings provide a rational design strategy for developing‌ tumor-microenvironment-responsive multimodal nanoplatforms.