Tracheal Targeted Nanogrid Delivery Systems of Dexamethasone Visualized by Single-Particle Tracing and Multiscale Pathological Mapping

Current clinical treatment of pulmonary diseases requires an advanced three-dimensional (3D) pathological atlas of the microenvironment, particularly the trachea, which is predominantly affected by lung disorders. In this study, the gridded cyclodextrin cross-links (GCC) exhibited enzymatic activities and served as a metal-free nanozyme. A specific biodistribution of GCC nanogrid around the trachea had been observed using a fluorescence micro-optical sectioning tomography system. The effective loading of dexamethasone (DEX) allowed for the construction of DEX@GCC nanogrid system, which exhibited a sustained-release profile and a preferable lung targeting in vivo. Additionally, DEX@GCC demonstrated improved efficacy in treating lipopolysaccharide-induced bronchitis of mice at lower dosages compared with the positive control. A 3D pathological assessment based on the micro-optical sectioning tomography system and high-content data analysis with machine learning validated the superiority of the GCC nanogrid for identifying inflammatory cells, quantifying tracheal wall thickness, and virtual endoscopy. In conclusion, the tracheal localization and ROS-responsive behaviors of the GCC nanogrid provide a cross-scale visualization strategy for evaluating nanoparticle biodistribution and advancing pulmonary disease treatment.