Nanoparticle-Mediated “Cut-Off and Clean-Up” Strategy for Neutrophil Manipulation in Acute Lung Injury Therapy

Polymorphonuclear neutrophils (PMNs) are pivotal in acute lung injury (ALI) due to their uncontrollable infiltration and intense inflammatory response. Therefore, we proposed a "cut-off and clean-up" strategy to manipulate PMNs for ALI treatment. To "cut off PMN supply", we consider occupying their binding sites on inflamed endothelium by targeting P-selectin. To precisely "clean up PMNs", we consider specifically inducing their apoptosis and minimizing damage to endothelium and pulmonary parenchyma. Thus, we constructed S-DE/GD, consisting of liposomes containing 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphoethanolamine (DOPE), sulfated hyaluronic acid (SHA) surface modification, and encapsulating glucose-modified doxorubicin (GD). For circulating PMNs, SHA with high P-selectin affinity can inhibit their infiltration. For infiltrated PMNs, the cleanup process involves two steps. First, GD escapes from endosomes utilizing DOPE and is then exocytosed into the lungs through the unidirectional transport of glucose. Subsequently, extruded GD is selectively taken up by infiltrated PMNs overexpressing glucose transporter-1. In ALI mouse model, S-DE/GD demonstrated significant therapeutic efficacy, indicating its potential as a promising strategy for ALI treatment.