An advanced inhalable dry powder, mucus-penetrating aerosol platform: Bridging Andrographolide delivery with clinical translation.

Effective aerosol drug delivery remains a challenge for treating pulmonary diseases due to physiological barriers such as mucus accumulation, biofilm formation, and rapid macrophage clearance. Here, we developed an inhalable honeycomb-like microsphere (HCLplga-Ab) aerosol platform using FDA-approved poly(lactic-co-glycolic acid) (PLGA) and a pore-forming agent. The platform encapsulates Andrographolide, a bioactive compound derived from traditional Chinese medicine, together with a chitosan-ambroxol coating to achieve mucus penetration, sequential drug release, and prolonged retention in the lungs. The large geometric diameter (∼10-15 μm) combined with an optimal aerodynamic size (∼2.57 μm) ensures deep lung deposition while evading alveolar macrophage clearance. In murine models of acute lung injury (ALI), bacterial pneumonia (Klebsiella pneumoniae), and fungal pneumonia (Candida albicans), HCLplga-Ab demonstrated enhanced mucus penetration and biofilm destruction, uniform and prolonged drug retention in the lungs, and significant reduction in inflammation and pathogen burden. This versatile platform bridges traditional medicine with modern aerosol technology, offering a promising solution for respiratory disorders and clinical translation.