A nano-immuno-cruise delivery system encapsulated lipid-integrated bilayer ameliorate acute lung injury by interfering neutrophil infiltration

Effective therapies for acute lung injury (ALI) are still lacking due to poor drug targeting and accumulation, inability to surmount the lung barrier. Nanosystem camouflaged with the membrane of immune cell and responsive lipids offers potential solution. In this study, we developed a nano-immuno-cruise drug delivery system (DDS) using the anti-inflammatory drug naringin (Nar) loaded reactive oxygen species (ROS)-responsive liposomes fused with activated neutrophil membranes (TK-NLP). The TK-NLP showed great targeting ability in both injured 2D epithelial cell model and 3D ALI model based on a 3D printed mimicking lung organ (mLO) with a dynamic environment on chip. Interestingly, TK-NLP could effectively inhibit the formation of platelet-neutrophil aggregates (PNAs), thereby showing great potential for suppressing PNA-mediated inflammatory cascades. Subsequently, in the mouse model of ALI, TK-NLP aggregate specifically at pneumonia sites and respond to the overexpressed ROS with the release of Nar, which reduced neutrophil infiltration and inflammatory factors secretion, protecting the integrity of the lung barrier to ameliorate ALI. Collectively, this nano-immuno-cruise DDS integrating immune camouflage, ROS-responsive controlled drug release, and targeted interference with PNAs formation, offers a novel and promising strategy for precision therapy and barrier repairment for ALI.