MOF-Based Nanoplatform Enables Synergistic Hypoxia-Activated Chemotherapy and Chemodynamic Therapy for Colon Cancer

Colon cancer is one of the most common and deadly malignancies. Although various treatment options are currently available, monotherapies often exhibit limited efficacy and are associated with severe side effects. The uneven distribution of hypoxia and the insufficient endogenous supply of hydrogen peroxide (H₂O₂) in the tumor microenvironment (TME) were addressed in this study by constructing a novel nanotherapy platform, TL@Cu/Z-PF. This platform codelivered β-lapachone (Lap) and the hypoxia-activated prodrug tirapazamine (TPZ) within a pH-responsive, biodegradable, copper-doped, zeolitic imidazolate framework. Furthermore, it was functionalized with polyethylene glycol-folic acid for targeted delivery and synergistic therapy. In the acidic TME, TL@Cu/Z-PF underwent pH-responsive degradation, releasing Cu²⁺ ions and therapeutic agents. The released Cu²⁺ ions consumed intracellular glutathione, generating Cu⁺ ions. Moreover, Lap underwent a redox cycle mediated by NQO1, which consumed oxygen and exacerbated tumor hypoxia, thereby activating TPZ. The H₂O₂ generated from this process served as a substrate for Cu⁺-mediated Fenton-like reactions, leading to the production of highly cytotoxic hydroxyl radicals and thereby enhancing the effect of chemodynamic therapy (CDT). The experimental findings confirmed that this strategy effectively integrates hypoxia-activated chemotherapy with CDT, resulting in significantly improved therapeutic outcomes compared to monotherapies.