Gold nanoparticles/Cu decorated metal–organic frameworks for synergistic photodynamic/ferroptosis cancer therapy

Photodynamic therapy (PDT) holds promise for cancer treatment by generating reactive oxygen species via photosensitizers (PSs) activated by specific wavelengths of light. However, the poor water solubility of PSs and the tumor microenvironment, characterized by high glutathione (GSH) levels and hypoxia, limit its efficacy against hypoxic tumors. To overcome these challenges, we developed a novel nano-reactor, Zr(Cu)-MOF@Au@DHA, to augment PDT-ferroptosis therapy. By incorporating Cu2+ into the porphyrin ring of PCN-224 and decorating it with gold nanoparticles, we enhanced the photocatalytic efficiency of the metal–organic framework (MOF). Additionally, dihydroartemisinin (DHA) was loaded onto the nano-reactor to boost the ferroptosis sensitivity of bladder cancer cells. Both in vitro and in vivo studies confirm that under laser irradiation, Zr(Cu)-MOF@Au@DHA significantly elevates oxidative stress, depletes GSH, and triggers DHA release, sensitizing tumor cells to ferroptosis and enhancing PDT-ferroptosis therapy for bladder cancer. This innovative nano-platform integrates near-infrared light-triggered PDT with chemotherapy to induce ferroptosis, addressing critical limitations in bladder cancer treatment.