Inhalable PD-L1-engineered hybrid cellular vesicles suppress excessive neutrophil activation and restore mitochondrial homeostasis to alleviate ischemia-reperfusion lung injury and pneumonia.

Lung ischemia-reperfusion injury and severe pneumonia represent major clinical challenges with high mortality rates and a lack of effective targeted therapies after lung transplant. Their pathogenesis involves multiple factors, including immune dysregulation, oxidative stress, and mitochondrial dysfunction, which limit the efficacy of single-target treatment strategies. This study developed a novel biohybrid nanovesicle system (Res-PD-L1@nmEVs) that integrates the inflammatory targeting capability of neutrophil membrane-derived vesicles, the tissue repair and immunomodulatory functions of PD-L1-overexpressing mesenchymal stem cell extracellular vesicles, and the mitochondrial protective effects of resveratrol. Following nebulized administration, the system demonstrated enhanced pulmonary accumulation and efficient uptake by injured epithelial cells. In vitro experiments confirmed that Res-PD-L1@nmEVs inhibited inflammation and oxidative stress, reduced apoptosis, and restored mitochondrial integrity by activating PINK1-mediated mitophagy and promoting mitochondrial repair, thereby mitigating hypoxia-reoxygenation-induced injury in lung epithelial cells. The delivery of PD-L1 via Res-PD-L1@nmEVs binding to PD-1 on neutrophil membranes suppressed neutrophil activation and alleviated the release of inflammatory factors. In rat models of lung ischemia-reperfusion injury and methicillin-resistant Staphylococcus aureus-induced pneumonia, nebulized administration of Res-PD-L1@nmEVs significantly attenuated lung tissue damage, inhibited neutrophil activation, reduced inflammatory cytokine release, improved alveolar barrier integrity, promoted the recovery of pulmonary function, and alleviated hypoxemia. Transcriptomic analysis revealed that the treatment synergistically enhanced energy metabolism and biosynthetic processes while suppressing inflammatory pathways. This study presents a comprehensive targeted strategy that simultaneously addresses immune dysregulation, oxidative damage, and metabolic dysfunction in inflammatory lung diseases, demonstrating significant potential for clinical translation.