Bimetallic oxide nanozyme-mediated depletion of glutathione to boost oxidative stress for combined nanocatalytic therapy

Although nanocatalytic therapy has become an emerging strategy for tumor treatment, the therapeutic effects of reactive oxygen species (ROS)-mediated treatment are still seriously limited by the inherent flaws of the enzymatic activities and the specific physicochemical properties of the tumor microenvironment (TME). Herein, we report an ultrasmall bimetallic oxide nanozyme (CuFe2O4@PEG, CFOs) for programmable multienzyme-like activities-primed combined therapy. Under the acidic condition, abundant highly toxic ROS can be generated through the peroxidase activity of CFOs with overexpressed hydrogen peroxide (H2O2) in the tumor. High metal ion utilization of bimetallic oxide nanozymes is related to the size effect and topological structure. Furthermore, glutathione peroxidase activity-initiated depletion of GSH disrupts the intracellular antioxidant defense system and further amplifies the oxidative stress in turn. Subsequently, oxygen generation originating from the catalase activity of CFOs relieves tumor hypoxia and achieves exceptional TME-customized therapeutic effects. Notably, the high photothermal effect (eta = 41.12%) of CFOs in the second near-infrared biological windows leads to the combinational inhibition of tumor growth. In summary, this report provides a paradigm for the rational design of TME-responsive and ROS-mediated nanocatalytic treatment, which is promising for achieving superior therapeutic efficiency. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study presents an ultrasmall bimetallic oxide nanozyme capable of generating abundant highly toxic reactive oxygen species (ROS) in the tumor microenvironment and exhibiting programmable multienzyme-like activities for customized therapy. The nanocatalyst, called CFOs, utilizes its peroxidase activity to produce ROS and depletes glutathione peroxidase activity to amplify oxidative stress. Moreover, the catalase activity of CFOs generates oxygen to relieve tumor hypoxia. Additionally, CFOs demonstrate a high photothermal effect for the combinational inhibition of tumor growth.