Immune-epithelial dual-targeting bilirubin nanoparticles for acute lung injury.

Acute lung injury (ALI) is characterized by dysregulated immune activation, oxidative stress, and disruption of the alveolar-capillary barrier, leading to pulmonary edema and acute respiratory failure. Effective pharmacological intervention remains limited, in part due to insufficient drug localization within the inflamed lung microenvironment. Here, we report a hyaluronic acid-bilirubin nanoassembly (HB@BN) designed to preferentially accumulate in inflamed pulmonary tissue and modulate immune-epithelial interactions through CD44-mediated cellular uptake. HB@BN integrates the intrinsic antioxidant and anti-inflammatory properties of bilirubin with inflammation-associated CD44 targeting. The nanoassembly effectively scavenged reactive oxygen species (ROS), activated the Nrf2/HO-1 pathway, and shifted macrophage polarization toward an anti-inflammatory phenotype in vitro. Following aerosol administration in a murine lipopolysaccharide-induced ALI model, HB@BN demonstrated enhanced pulmonary retention, attenuated inflammatory cytokine production, reduced edema and collagen deposition, and improved histological injury scores. Collectively, these results indicate that coordinated modulation of macrophage-driven inflammation and epithelial barrier dysfunction through redox-responsive nanodelivery represents a promising strategy for the management of acute inflammatory lung injury.