Multistimulus-responsive oxidative stress/ferroptosis combination anti-tumor nano-enzyme constructed based on glucose oxidase and PEG-PAA.

Enzymes show excellent specificity and high efficiency in the treatment of various diseases, how to avoid inactivation during human circulation and improve the transfection are still challenges. Based on the importance of glucose enzymes (GOx) in the process of ferroptosis, we developed a nano-enzyme system containing GOx based on the self-assembly of near-infrared (NIR)-responsive Prussian blue (PB) and the thermosensitive polymer PEG-P(AAm-co-AN) (PEG-PAA). PB provided both photothermal effects and peroxidase-like activity, while the PEG-PAA shell shielded and protected GOx. Upon NIR irradiation, the PB/GOx@PAA-PEG nanoparticles exploited PB's photothermal properties to reach the upper critical solution temperature (UCST) of PEG-PAA, triggering a hydrophilic-hydrophobic transition in the polymer shell. This transition caused GOx exposed to glucose, switching on the conversion of glucose into hydrogen peroxide, which was further catalyzed into hydroxyl radical (•OH) by PB. Cell-based experiments investigated the biocompatibility and intracellular ROS levels after incubation with PB/GOx@PAA-PEG nanoparticles. The cytotoxicity and the mechanism of cell death were further explored by using various indicators such as vitamin E (VE), glutathione (GSH). This study demonstrated a low side-effect, high-efficiency anti-tumor nano-enzyme system with synergistic anti-tumor effects of oxidative stress and ferroptosis, providing effective strategies for multiple tumor therapies.