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@MnO 2 ). The coated MnO 2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O 2 from H 2 O 2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H 2 O 2 for the subsequent Cu + -based Fenton-like reaction. Meanwhile, the Cu 2+ 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 H 2 O 2 by enzyme catalysis to produce a toxic hydroxyl radical ( • OH), and singlet oxygen ( 1 O 2 ) is synchronously generated from combination with Cu +, O 2, and H 2 O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn 2+ -induced T 1 -weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224(Cu)-GOD@MnO 2 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.