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

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.