GSH-Activated Cu-TCPP(Zn)/Ti3C2Tx Nanozymes for Fluorescence Imaging-Guided Synergistic Photodynamic/Chemodynamic Therapy of Oral Squamous Cell Carcinoma

Photodynamic therapy (PDT) holds promise for oral squamous cell carcinoma (OSCC) but is limited by the tumor microenvironment─specifically hypoxia, elevated glutathione (GSH), and the lack of tumor-selective photosensitizer activation. To overcome these barriers, we developed a GSH-activated nanoplatform Cu-TCPP(Zn)/Ti3C2Tx for fluorescence imaging-guided synergistic photodynamic/chemodynamic therapy (PDT/CDT). The system is constructed from two-dimensional Cu-TCPP(Zn) MOF nanosheets, where Cu2+ and Zn2+ completely quench the fluorescence and PDT activity of TCPP and surface-anchored Ti3C2Tx MXene. In the TME, overexpressed GSH reduces Cu2+ to Cu+ and abstracts Zn from the Zn–N4 complex, triggering nanocomposite disintegration to restore fluorescence, activate PDT, and simultaneously deplete GSH to reduce antioxidant defense. The resulting Cu+ catalyzes a Fenton-like reaction with endogenous H2O2 to generate •OH for CDT, while Ti3C2Tx acts as a catalase-like nanozyme, decomposing H2O2 into O2 to alleviate hypoxia, promote charge transfer, improve the utilization efficiency of photogenerated electrons, and enhance PDT efficacy. In vitro, the platform showed excellent biocompatibility and GSH-responsive activation, inducing 41.21% apoptosis in CAL-27 cells under 660 nm laser irradiation, significantly outperforming controls. In vivo, the nanocomposite accumulated efficiently in tumors via the EPR effect, suppressed tumor growth, and exhibited no observable systemic toxicity. This work provides a TME-responsive theranostic platform that integrates tumor-specific activation, GSH depletion, hypoxia alleviation, and enhanced ROS generation for precise and effective OSCC treatment.