Chunxing Xian, Jingdi Chen, Xiang Li, Ruicong Wang, Yu Chen, Yanwu Liu, Xiang He, Jingjing Zhao, Taoran Wang, Jiakai Gao, Mingru Zhang, Lei Zhou, Long Bi
The First Affiliated Hospital Of Air Force Medical University, Xian, China.
Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
Int J Pharm. 2025 Oct 15;683:126067. doi: 10.1016/j.ijpharm.2025.126067. Epub 2025 Aug 14.
The biofilm formed by methicillin-resistant Staphylococcus aureus (MRSA) on orthopedic implants substantially impedes the penetration of antimicrobial agents, leading to recurrent bone infections and imposing a significant financial burden on patients. Prior research has demonstrated that Staphylococcus epidermidis, a conditional pathogen, exhibits low toxicity in deep tissues and effectively suppresses MRSA growth in superficial tissues. However, the mechanism by which S. epidermidis inhibits MRSA, as well as its capacity to suppress MRSA proliferation or biofilm formation in deep tissues, requires further elucidation. This study hypothesizes that S. epidermidis extracellular vesicles (SE-EVs) may play a pivotal regulatory role in this process. To validate this hypothesis, we obtained SE-EVs and observed the biological effects of the vesicles on MRSA. In vitro experimental results revealed that SE-EVs markedly inhibited MRSA proliferation and biofilm formation. Furthermore, in vivo experiments demonstrated that SE-EVs at a concentration of 1 μg/mL effectively suppressed MRSA-associated implant infections and biofilm formation. We further elucidated the primary mechanism by which SE-EVs inhibit MRSA biofilms through RNA sequencing. The sequencing results suggested that this effect is achieved by suppressing the cationic antimicrobial peptide (CAMP) resistance signaling pathway, which plays a critical role in biofilm formation. Additionally, both in vitro and in vivo experiments confirmed that SE-EVs do not induce inflammation or cause damage to vital organs. In summary, this study is the first to reveal the natural anti-MRSA biofilm properties of SE-EVs, providing a theoretical foundation for their potential application in treating MRSA-associated implant bone infections.
耐甲氧西林金黄色葡萄球菌（MRSA）在骨科植入物上形成的生物膜严重阻碍了抗菌剂的渗透，导致骨感染反复发作，并给患者带来巨大经济负担。先前的研究表明，表皮葡萄球菌作为一种条件致病菌，在深部组织中毒性较低，且能有效抑制浅表组织中MRSA的生长。然而，表皮葡萄球菌抑制MRSA的机制及其在深部组织中抑制MRSA增殖或生物膜形成的能力尚需进一步阐明。本研究假设表皮葡萄球菌细胞外囊泡（SE-EVs）可能在此过程中发挥关键调节作用。为验证这一假设，我们获取了SE-EVs并观察了其对MRSA的生物学效应。体外实验结果显示，SE-EVs显著抑制了MRSA的增殖和生物膜形成。此外，体内实验表明，浓度为1μg/mL的SE-EVs能有效抑制与MRSA相关的植入物感染和生物膜形成。我们通过RNA测序进一步阐明了SE-EVs抑制MRSA生物膜的主要机制。测序结果表明，这种效应是通过抑制阳离子抗菌肽（CAMP）抗性信号通路实现的，该通路在生物膜形成中起关键作用。此外，体外和体内实验均证实，SE-EVs不会诱导炎症或对重要器官造成损害。综上所述，本研究首次揭示了SE-EVs天然的抗MRSA生物膜特性，为其在治疗与MRSA相关的植入物骨感染中的潜在应用提供了理论基础。
