Neutrophil‐Mimicking Nanozyme with Cascade Catalytic Releasing Nitric Oxide and Signet Oxygen Property for Synergistic Bimodal Therapy of Methicillin‐Resistant Staphylococcus Aureus Infections

Abstract Recently, chloroperoxidase (CPO)‐mediated enzyme dynamic therapy (EDT) by mimicking the antipathogen function of neutrophils via generating highly active signet oxygen ( ¹ O ₂ ) has attracted great interest in biomedical applications. However, the therapeutic efficiency of EDT is largely restricted by the low CPO delivery efficiency and insufficient hydrogen peroxide (H ₂ O ₂ ) supply. In the present work, a neutrophil‐mimicking nanozyme of MGBC with high CPO delivery efficiency, H ₂ O ₂ self‐supply, and enzyme‐cascade catalytic properties is designed for high‐efficient treatment of methicillin‐resistant Staphylococcus aureus ( MRSA ) infections. In the infection microenvironment, MGBC can effectively catalyze glucose to self‐supply substantial H ₂ O ₂ , which enables long‐lasting ¹ O ₂ generation via the CPO‐mediated catalytic reaction. At the meantime, MGBC can also catalyze H ₂ O ₂ to sustainably release NO for gas therapy (GT), which synergistically strengthens the therapeutic effect of EDT. As a result, MGBC displayed effective MRSA ‐killing and MSRA biofilms‐eradicating properties, and high efficiency in treating both MRSA infected full‐thickness excision wounds and subcutaneous MRSA infection by exerting the synergistic bimodal EDT/GT therapeutic effects. In‐depth mechanism study revealed that the synergistic EDT/GT antibacterial effects of MGBC can attenuate the drug resistance and toxicity of MRSA by significantly downregulating quorum sensing, multidrug efflux, virulence, and biofilm formation‐related genes.