Coordination‐Driven Nanomedicine Mitigates One‐Lung Ventilation‐Induced Lung Injury via Radicals Scavenging and Cell Pyroptosis Inhibition

Abstract One‐lung ventilation (OLV) during thoracic surgery often leads to post‐operative complications, yet effective pharmacological interventions are lacking. This study reports a baicalin‐based metal‐coordination nanomedicine with disulfiram (DSF) co‐loading to address one‐lung ventilation‐induced lung injury and reperfusion injury (OLV‐LIRI). Baicalin, known for its robust antioxidant properties, suffers from poor water solubility and stability. Leveraging nanotechnology, baicalin's coordination is systematically explored with seven common metal ions, designing iron/copper‐mediated binary coordination nanoparticles to overcome these limitations. The self‐assembled nanoparticles, primarily formed through metal coordination and π–π stacking forces, encapsulated DSF, ensuring high colloidal stability in diverse physiological matrices. Upon a single‐dose administration via endotracheal intubation, the nanoparticles efficiently accumulate in lung tissues and swiftly penetrate the pulmonary mucosa. Intracellularly, baicalin exhibits free radical scavenging activity to suppress inflammation. Concurrently, the release of Cu 2+ and DSF enables the in situ generation of CuET, a potent inhibitor of cell pyroptosis. Harnessing these multifaceted mechanisms, the nanoparticles alleviate lung injury symptoms without notable toxic side effects, suggesting a promising preventive strategy for OLV‐LIRI.