GSH-Activated Cu-TCPP(Zn)/Ti ₃ C ₂ T _<i>x</i> 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)/Ti₃C₂T_<i>x</i> 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 Ti₃C₂T_<i>x</i> 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 Ti₃C₂T_<i>x</i> 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.