Coupling doping and localized surface plasmon resonance toward acidic pH-preferential catalase-like nanozyme for oxygen-dominated synergistic cancer therapy

Hypoxia increases patient treatment resistance and favors cancer progression. Nanozymes have received unprecedented attention in alleviating hypoxia via catalase (CAT)-mimicking catalytic reaction. However, the oxygen production capability of CAT-like nanozymes undergoes the deficiency and even absolute loss in acidic tumor microenvironment. Herein, we propose a doping-localized surface plasmon resonance (LSPR) coupling strategy to shatter the acidic pH limitation and reinforce the catalytic activity of CAT-like nanozyme for oxygen-dominated synergistic cancer therapy. Platinum-doped plasmonic gold nanostar modified with glucose oxidase (Pt-AuNS-GOx) is constructed as a proof-of-concept. Density functional theory calculations reveal the *O-assisted and *OH-assisted CAT-like reaction paths in Pt-AuNS-GOx, and demonstrate that Pt doping-induced energy barrier reduction accounts for the oxygen generation in acidity. Furthermore, the CAT-like reaction kinetics of Pt-AuNS-GOx can be significantly enhanced upon plasmon irradiation resulted from the excited hot electrons and local heating accompanied with LSPR decay. Such outstanding acidic pH-preferential oxygen generation capability of Pt-AuNS-GOx significantly boosts the efficiency of synergistic tumor aerobic therapeutics of glutathione oxidation-medicated oxidative stress and GOx-activated starvation in vitro. Remarkably, Pt-AuNS-GOx substantially reverses the hypoxic microenvironment of tumor tissue, and enables greatly accelerated apoptosis and suppressed metastasis of cancer in vivo, possessing conspicuous therapeutic efficiency. The proposed doping-LSPR coupling strategy offers a powerful modality to modulate the restricted reaction pH of CAT-like nanozymes, and provides a paradigm shift for hypoxia alleviation-boosted cancer synergistic treatment.