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

Abstract 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.