Copper nanoparticles-anchored UiO-66 nanoagent for glutathione-depleted chemo/chemodynamic synergistic therapy

Metal-organic frameworks (MOFs) have emerged as promising potential therapeutics for treating cancer, being primed for hybridization and postsynthetic modification to achieve chemodynamic therapy (CDT) by Fenton/Fenton-like chemistry that converts endogenous hydrogen peroxide into hydroxyl radicals (•OH). The therapeutic efficacy of CDT can be constrained by the redox homeostasis of cancer cells, particularly intracellular glutathione (GSH), which acts as a scavenger for reactive oxygen species (ROS). Herein, we describe the design and synthesis of a UiO-66 nanoagent with encapsulated copper nanoparticles, that is further loaded with carboplatin (CA), and functionalised with maleimide (Mal) and a poly(ethylene glycol) (PEG) surface: CA@UiO@Cu@Mal@PEG. Comprehensive in vitro experiments demonstrate that, on internalization by cancer cells, the nanoagent is expected to be decomposed by intracellular phosphate. The release of CA and Cu nanoparticles induces chemo/chemodynamic synergistic cytotoxicity, causing mitochondrial damage and ATP reduction, whilst Mal depletes GSH via Michael addition, thereby weakening the cancer's intrinsic antioxidant activity and so enhancing CDT efficiency. This work represents a new dual regulated redox-dyshomeostasis strategy for enhancing cancer therapeutic efficiency via intracellular •OH generation and GSH depletion.