Sono‐Triggered Biomimetically Nanoantibiotics Mediate Precise Sequential Therapy of MRSA‐Induced Lung Infection

Abstract Bacterial‐induced lower respiratory tract infections are a growing global health concern, exacerbated by the inefficacy of conventional antibiotics and delivery methods to effectively target the lower respiratory tract, leading to suboptimal therapeutic outcomes. To address this challenge, this work engineers PBP2a antibody‐presenting membrane nanovesicles (AMVs) specifically designed to target the penicillin‐binding protein variant on the surface of methicillin‐resistant Staphylococcus aureus (MRSA). Concurrently, this work develops pure ciprofloxacin nanoparticles (NanoCip) that, for the first time, exhibits exceptional self‐generated sonodynamic properties, attributed to hydrogen‐bond‐driven self‐assembly, while maintaining their inherent pharmacological efficacy. These NanoCip particles are integrated with AMVs to create a novel biomimetic nanomedicine, AMV@NanoCip. This formulation demonstrated remarkable MRSA‐targeting affinity in both in vitro and in vivo models, significantly enhancing antibacterial activity. Upon ultrasound stimulation, AMV@NanoCip achieves over 99.99% sterilization of MRSA in vitro, with a reduction exceeding 5.14 Log CFU. Prokaryotic transcriptomic analysis further elucidates the synergistic mechanisms by which AMV@NanoCip, coupled with ultrasound, disrupts the MRSA exoskeleton. In a MRSA‐induced pneumonia animal model, AMV@NanoCip+US results in a substantial bacterial load reduction in the lungs (99.99%, 4.02 Log CFU). This sequential treatment strategy (adhesion‐membrane disruption‐synergistic therapy) offers significant promise as an innovative therapeutic approach for combating bacterial infections.