Multi-enzymatic catalysis copper ceria-polyphenol nanozyme for balancing peroxidase catalysis and reactive oxygen scavenging: a synergistic strategy for enhancing drug-resistant bacteria eradication

Strong catalysis and novel copper-induced cell death enable copper-based nanozymes to present good bactericidal capacity against antibiotic-resistant pathogens, but their aspect of the balance between low ROS and low-dose antibacterial performance remains a significant challenge. Herein, an innovative copper/cerium (Cu/Ce)-doped metal-polyphenol network nanozyme (CCP) was synthesized for synergistically modulating the multi-enzymatic activities and enhancing methicillin-resistant Staphylococcus aureus (MRSA) eradication, where Cu and Ce individually decorated on carbon nanosheet skeleton. Benefited from the Cu/Ce dual-site structure, CCP exhibited remarkable multi-enzymatic (superoxide dismutase-, peroxidase-, glutathione peroxidase-, and nicotinamide adenine dinucleotide peroxidase-like) and • OH scavenging activities. While possessing negative surface charge and good biocompatibility, CCP displayed excellent antibacterial capability. With the addition of H 2 O 2 , CCP achieved complete killing against MRSA at 30 µg·mL − 1 , whose process exhibited rather low ROS content, suggesting the balanced ability of CCP between peroxidase catalysis and ROS scavenging. Surprisingly, CCP could eradicate ~80% MRSA biofilms at 60 µg·mL − 1 without H 2 O 2 , probably attributed to the weak acidic, H 2 O 2 - and GSH-rich biofilm microenvironment for enhancing the peroxidase and glutathione peroxidase catalyses. Mechanism explorations revealed that the prominent antibacterial behavior was associated with the Cu/Ce synergistic effect on blocking bacterial cell membrane construction and cell wall biosynthesis, breaking ATP and protein synthesis, inducing protein toxicity stress and promoting TCA cycle to react with toxic Cu + /Ce 3+ for cuproptosis-like death. Furthermore, shrimp preservation experiment demonstrated the great potential of CCP in food preservation field. This work paved a new avenue for future investigation of multifunctional Cu-based nanozymes.