Engineering Neutrophil Vesicles for Synergistic Protection against Ischemia/Reperfusion Injury after Lung Transplant

Lung transplantation (LTx) is a life-saving procedure for patients with end-stage respiratory failure; however, primary graft dysfunction (PGD), primarily induced by ischemia/reperfusion injury (IRI), remains a major complication. Although ex vivo lung perfusion (EVLP) improves preservation, clinical translation remains challenging owing to IRI complexity. Here, a novel approach is presented to mitigate lung IRI by developing of neutrophil-derived ROS-responsive cellular vesicles (SOD2-Fer-1@CVs). This hybrid system integrates superoxide dismutase 2 (SOD2)-overexpressing neutrophil nanovesicles with ROS-responsive liposomes loaded with ferrostatin-1 (Fer-1), a potent ferroptosis inhibitor. SOD2-Fer-1@CVs enabled targeted delivery to inflamed tissues and high oxidative stress environments, enabling ROS-triggered release of SOD2 and Fer-1. The SOD2-Fer-1@CVs system mechanistically targeted the core pathological pathways of IRI, including oxidative stress alleviation, adsorption and neutralization of pro-inflammatory cytokines, ferroptosis suppression, and restoration of endothelial barrier integrity, with concurrent promotion of macrophage M2 polarization. Using the proprietary small-animal EVLP platform, the therapeutic administration of SOD2-Fer-1@CVs significantly mitigated of reperfusion-related pathologies and improved graft performance, including enhanced oxygenation, reduced airway resistance, and restored lung compliance, attenuating lung injury after LTx. This study established a novel nanotherapeutic strategy that synergizes with EVLP to address multifactorial IRI, showing high translational potential for improving donor lung quality and LTx outcomes.