A novel cyanine photosensitizer for sequential dual-site GSH depletion and ROS-potentiated cancer photodynamic therapy.

The efficacy of photodynamic therapy (PDT) is often limited by the reductive microenvironment in tumor cells due to the high level of glutathione (GSH) and glutathione peroxidase 4 (GPX4), which maintain redox homeostasis. Therefore, designing a GSH-responsive photosensitizer that depletes intracellular GSH is a promising strategy to enhance PDT selectivity and efficacy. Herein, we present a GSH-selective sequentially responsive theranostic photosensitizer, Cy-Res. This cyanine agent targeting mitochondria effectively depletes two GSH molecules, leading to the generation of abundant ROS and exacerbating oxidative stress. Additionally, it achieves an 80-fold fluorescence enhancement upon response to GSH, enabling selective imaging of tumor cells. By mitigating GSH's impact on PDT, Cy-ResNPs achieves synergistic and efficient PDT treatment of invasive melanoma under low-power irradiation (808 nm, 80 mW/cm). The inhibitory processes downregulate GPX4, increase apoptotic proteins like Bax, and promote mixed cell death involving both ferroptosis and apoptosis. Overall, this study offers new insights and strategies for the development of GSH-responsive theranostic agents, highlighting their potential for application in tumor diagnosis and therapy.