Fusiform-Like Copper(II)-Based Metal–Organic Framework through Relief Hypoxia and GSH-Depletion Co-Enhanced Starvation and Chemodynamic Synergetic Cancer Therapy

The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper(II)-based tetrakis(4-carboxy phenyl)porphyrin (TCPP) nanoscale metal-organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224(Cu)-GOD@MnO₂). The coated MnO₂ layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O₂ from H₂O₂ to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H₂O₂ for the subsequent Cu⁺-based Fenton-like reaction. Meanwhile, the Cu²⁺ chelated to the TCPP ligand is converted to Cu⁺ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu⁺ reacts with the plentiful H₂O₂ by enzyme catalysis to produce a toxic hydroxyl radical (^•OH), and singlet oxygen (¹O₂) is synchronously generated from combination with Cu⁺, O₂, and H₂O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn²⁺-induced T₁-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224(Cu)-GOD@MnO₂ nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.