Cinnamaldehyde-loaded gold nanobipyramids for dual-amplification of oxidative stress to enhance cancer catalytic therapy.

Various inorganic nanozymes have been developed to generate highly reactive hydroxyl radicals (˙OH) through enzyme-mimetic catalytic activity for applications in catalytic therapy. However, the elevated levels of the antioxidant glutathione (GSH) in tumor cells can effectively neutralize ˙OH, thereby diminishing the therapeutic efficacy of these nanozymes, a prevalent issue in catalytic therapy. In this study, gold nanobipyramids (GNB) were integrated with cinnamaldehyde (CA) via electrostatic adsorption and hydrogen bonding to develop a nanozyme platform (GNB@CA) capable of tumor-specifically enhancing oxidative stress. GNB possess intrinsic peroxidase (POD)-like activity, enabling the conversion of endogenous hydrogen peroxide (H2O2) into highly toxic ˙OH for catalytic therapy. Additionally, their photothermal conversion capability further boosts catalytic efficiency. CA exerts its effects through dual mechanisms: its α,β-unsaturated aldehyde group covalently binds to the thiol group of GSH via a Michael addition reaction, leading to a reduction in intracellular GSH and thereby weakening the antioxidant defense of tumor cells. Additionally, CA induces mitochondrial dysfunction by lowering the mitochondrial membrane potential, subsequently triggering tumor cell apoptosis. In vivo studies demonstrate that GNB@CA can effectively eradicate triple-negative breast cancer (TNBC) in mice through synergistic induction of robust oxidative stress. This research offers valuable insights for the design of nanozymes in catalytic cancer therapy.