GSH-responsive triple-action photosensitizer nanoplatforms orchestrate cuproptosis-ferroptosis synergy to potentiate antitumor PDT efficacy.

Multimodal targeted combination therapy that harnesses synergistic effects has emerged as a transformative paradigm in cancer therapy, progressively replacing traditional monotherapy. Herein, we report a tumor microenvironment (TME)-responsive multifunctional nanoplatform Cu-Ce6@DHA NPs (CCD NPs), which is self-assembled through the coordination of Cu²⁺, the antitumor drug dihydroartemisinin (DHA), and the photosensitizer chlorin e6 (Ce6). This nanoplatform enables the near-infrared-triggered combination of cuproptosis and ferroptosis for tumor treatment. Upon internalization by tumor cells, these nanoparticles undergo glutathione (GSH)-triggered disintegration, releasing their encapsulated payloads within the TME. The released Ce6 mediates potent photodynamic therapy (PDT) under laser irradiation, and DHA undergoes GSH-dependent activation to generate cytotoxic reactive oxygen species (ROS) and suppresses glutathione peroxidase 4 (GPX4), thereby amplifying ferroptotic cell death. Concurrently, the released copper ions deplete intracellular GSH and further inhibit GPX4, which exacerbates lipid peroxidation and promotes ferroptosis. Notably, the intracellular accumulation of copper ions disrupts mitochondrial metabolism by destabilizing iron-sulfur cluster (Fe-S) proteins and inducing oligomerization of lipoylated lipoylated dihydrolipoamide S-acetyltransferase (DLAT), ultimately triggering cuproptosis. Therefore, our findings establish a novel nanoplatform that simultaneously exploits metabolic vulnerabilities (via cuproptosis), redox imbalances (via ferroptosis), and photodynamic effects, providing a promising multimodal therapeutic strategy for cancer treatment.