Glutathione-Responsive Inhalable Nanotherapeutics for Targeted Macrophage Reprogramming in Chronic Obstructive Pulmonary Disease

Chronic inflammation of the airways plays a crucial role in disease progression and symptom exacerbation in patients with chronic obstructive pulmonary disease (COPD). Nitric oxide (NO) relaxes airway smooth muscle and regulates the inflammatory response. The multifunctional therapeutic effects of NO are highly attractive for COPD treatment. However, the practical difficulties in long-term and targeted administration remain a limitation. This work presents an inhaled nanotherapeutic, termed AIR (Anti-Inflammatory Relaxer), engineered for targeted NO delivery to proinflammatory M1 macrophages. AIR is constructed from dendritic mesoporous silica nanoparticles (DMSNs) functionalized with hyaluronic acid (HA) and diazeniumdiolates (NONOates). HA enables selective targeting of CD44-overexpressing M1 macrophages, thereby leading to their polarization into anti-inflammatory phenotypes. Moreover, disulfide bonds in AIR are cleaved by intracellular glutathione, which is present at millimolar concentrations, ensuring excellent biocompatibility. Overall, these inhaled nanotherapeutics have great potential in relieving chronic inflammation in COPD while reducing bioaccumulation in the lungs.