Poly(Ionic Liquid) Nanofibers Suppress S. aureus Membrane Vesicle-Induced NETosis to Mitigate Wound and Lung Damage.

Staphylococcus aureus membrane vesicles (MVs) cause host injury and excessive inflammation, yet their pathological roles and clearance strategies remain undefined. Guided by molecular dynamics simulations of MV-polymer interactions, we engineered imidazolium-based poly(ionic liquid) (PIL) electrospun nanofibers for targeted MV interception. Among multiple formulations, PIL-C4 demonstrated optimal performance, combining potent antibacterial activity, robust adsorption of methicillin-resistant S. aureus (MRSA) MVs and their virulence factors, minimal cytotoxicity, and inhibition of resistance transmission. In vivo, PIL-C4 attenuated MV-induced neutrophil extracellular trap (NET) formation (NETosis) and vascular leakage, thereby reducing purulent-exudative wound injury and preventing systemic organ damage, including fatal lung injury. Notably, DNase-mediated NET degradation alone failed to rescue MV pathology, underscoring the necessity of direct MV clearance. This study uncovers previously unrecognized NETosis-driven phenotypes of S. aureus MVs-local purulent-exudative wound injury and systemic lethal lung damage-and establishes a polymer-based clearance strategy with translational potential for infection control.