Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou, 510632, China.
Small. 2024 Nov;20(45):e2403527. doi: 10.1002/smll.202403527. Epub 2024 Jul 19.
Recently, chloroperoxidase (CPO)-mediated enzyme dynamic therapy (EDT) by mimicking the antipathogen function of neutrophils via generating highly active signet oxygen (O) 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 (HO) supply. In the present work, a neutrophil-mimicking nanozyme of MGBC with high CPO delivery efficiency, HO 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 HO, which enables long-lasting O generation via the CPO-mediated catalytic reaction. At the meantime, MGBC can also catalyze HO 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.
最近，通过模拟中性粒细胞的抗病原体功能生成高活性单线态氧（O），氯过氧化物酶（CPO）介导的酶动态治疗（EDT）在生物医学应用中引起了极大的兴趣。然而，EDT 的治疗效率在很大程度上受到 CPO 传递效率低和 H2O2（HO）供应不足的限制。在本工作中，设计了一种具有高 CPO 传递效率、HO 自供应和酶级联催化特性的中性粒细胞模拟纳米酶 MGBC，用于高效治疗耐甲氧西林金黄色葡萄球菌（MRSA）感染。在感染微环境中，MGBC 可以有效地催化葡萄糖自供应大量的 HO，这使得通过 CPO 介导的催化反应能够持续产生 O。与此同时，MGBC 还可以催化 HO 持续释放 NO 用于气体治疗（GT），这协同增强了 EDT 的治疗效果。结果，MGBC 表现出有效的 MRSA 杀伤和 MRSA 生物膜消除特性，并通过发挥协同双模态 EDT/GT 治疗效果，高效治疗 MRSA 全层切除伤口感染和皮下 MRSA 感染。深入的机制研究表明，MGBC 的协同 EDT/GT 抗菌作用通过显著下调群体感应、多药外排、毒力和生物膜形成相关基因来减轻 MRSA 的耐药性和毒性。
