Restorative endothelium and polarization-assisted inflammatory regulation nanomedicine (REPAIR) for acute lung injury treatment

ABSTRACT Acute lung injury (ALI) is marked by uncontrolled inflammation and excessive immune cell infiltration, ultimately causing endothelial barrier disruption and impaired pulmonary function. To counteract these pathological processes, we develop a Restorative Endothelium and Polarization-Assisted Inflammatory Regulation nanomedicine (REPAIR) that integrates endothelial protection with alveolar macrophage reprogramming. REPAIR is fabricated by loading the P2X7 receptor‌ (P2X7R) antagonist A740003 into apoptotic NIH3T3 cell vesicles (Apo-Vesicles), thereby combining apoptotic cell-derived “eat-me” signals with targeted inhibition of P2X7R-mediated inflammatory pathways. Benefiting from its apoptotic cell-mimetic surface, REPAIR exhibits markedly enhanced uptake by alveolar macrophages (AMs), driving the transition of pro-inflammatory M1 macrophages toward an anti-inflammatory M2 phenotype. At the same time, the released A740003 efficiently suppresses P2X7R activation, preventing macrophage necrosis and preserving endothelial vascular endothelial (VE)-cadherin to maintain vascular barrier integrity. In vitro and in vivo studies further confirm that REPAIR substantially reduces inflammatory cytokine production, limits macrophage necrosis, and stabilizes endothelial junctions through the synergistic interplay of apoptotic mimicry and P2X7R antagonism. These results highlight REPAIR as a promising and mechanistically comprehensive nanotherapeutic strategy for ALI and other inflammation-driven pulmonary diseases.