Inhalable Macrophage Membrane-Camouflaged Hyperbranched Polymeric Nanoparticles for Acute Lung Injury Treatment

Abstract

Acute lung injury (ALI) involves a vicious cycle of excessive reactive oxygen species (ROS) and inflammatory cytokines that current therapies have failed to address comprehensively. Here, we developed an inhalable biomimetic nanoplatform (M2M-SNPs) by coating ROS-responsive nanoparticles (SNPs) with M2 macrophage membranes (M2Ms), creating a dual-action platform that simultaneously scavenges ROS and neutralizes cytokines. More importantly, the M2M shell mediates targeted delivery to inflamed pulmonary tissues via natural homing properties, and the SNP core maintains receptor activity by preventing oxidative damage. In lipopolysaccharide (LPS)-induced ALI animal models, inhaled M2M-SNPs exhibited 2-fold-greater pulmonary accumulation than uncoated nanoparticles and achieved 58% ROS scavenging and 62-92% cytokine adsorption, significantly improving inflammatory infiltration and pulmonary edema. Transcriptome sequencing analysis further confirmed that M2M-SNPs mitigated ALI through systemic modulation of immune-inflammatory networks, particularly in IL-17 and TNF signaling pathways. This study provides a promising nanotherapeutic strategy for inflammatory respiratory diseases.

Keywords: acute lung injury; cell membrane nanoparticles; cytokine storm; drug delivery; extracellular vesicles.