Nanogrid drug delivery systems developed for precise lung inflammation treatment

Understanding how drug delivery systems distribute in vivo remains a major challenge in developing nanomedicines. Especially in the lung, the complex and dynamic microenvironment often limits the effectiveness of existing approaches.

“Structural pharmaceutics” has been introduced as a new strategy to connect nanoparticle structures with physiological structures through advanced three-dimensional (3D) imaging and cross-scale characterizations.

In a study published in ACS Nano, a team led by Yin Xianzhen from the Lingang Laboratory and Zhang Jiwen from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences developed a precise targeting strategy for tracheal inflammation.

The strategy uses nanogrid-based delivery systems composed of gridded cyclodextrin cross-links (GCC), and enables multiscale 3D visualization and in-depth pharmacodynamic evaluation with micro-optical sectioning tomography (MOST) and fluorescence MOST (fMOST) systems.

Researchers designed the GCC carrier using cross-linked cyclodextrins with effective reactive oxygen species scavenging abilities. They labeled the nanogrid with Rhodamine 110 and tracked its journey after tail vein injection in mice using single-particle tracing and 3D whole-lung imaging.

Surprisingly, the nanogrid showed significant accumulation along the outer wall of the trachea, a feature rarely observed with conventional nanoparticles.

When loaded with dexamethasone (DEX), a commonly used corticosteroid, the GCC system not only prolonged drug retention in vivo but also displayed a controlled-release profile.

The formulation also showed strong anti-inflammatory effects in a lipopolysaccharide-induced bronchitis mouse model. Mice treated with DEX@GCC recovered body weight more rapidly, exhibited improved lung function, and showed significantly reduced inflammatory markers in bronchoalveolar lavage fluid compared to free DEX (higher dose) or model groups.

To visualize these therapeutic outcomes, researchers developed a whole-lung 3D pathological atlas. Combining fluorescence imaging and machine learning-assisted cell recognition, they reconstructed spatial maps of inflammation and quantified structural changes such as tracheal wall thickening.

Virtual endoscopic imaging allowed them to “see” the inside of diseased tracheas and quantitatively assess effects in a noninvasive yet highly detailed manner. These techniques helped confirm the structural repair and anti-inflammatory efficacy of DEX@GCC at both tissue and cellular levels.

This study provides a new framework for understanding how nano-drugs behave in complex biological environments by integrating the concept of “structural pharmaceutics” with 3D organ-level mapping.

The 3D pathology reveals spatiotemporal patterns of progressive lesions to support phenotype screening, target discovery and intervention design.