Engineering the Micro‐Nano Hierarchical Spray Hydrogel for Acute Lung Injury Therapy

Acute lung injury (ALI) poses a significant threat to human health, yet specific treatments remain elusive. Despite extensive research efforts, drug delivery to the lungs and reliable preclinical models are major challenges. To address these issues, a novel micro-nano hierarchical spray hydrogel is developed with the enhanced targeting ability for treating ALI. The hierarchical nanocomposite hydrogel is characterized with ordered micro-nanostructure, composing of spray hydrogel and astaxanthin nanoparticles (ASX-NPs). Astaxanthin, a natural active ingredient derived from algae, is nano-encapsulated to produce ASX-NPs, which significantly improves bioavailability. ASX-NPs are found to efficiently target the mitochondria and significantly relieve the inflammatory responses in human lung organoid-based inflammatory models by downregulating inflammation- and oxidative stress-related pathways and upregulating mitochondrial energy metabolism. In ALI mice, the spray hydrogel adheres to the tracheal mucosa and rapidly releases ASX-NPs upon inhalation. Released ASX-NPs are endocytosed to alleviate the inflammation and promote ALI recovery. The findings suggest that this hierarchical hydrogel system offer a promising alternative for ALI treatment, and can expand the applications of human organoids in disease modeling and drug discovery.