Inhalable Acid-Responsive Methane Nanocapsule for Remodeling Fibrogenic Microenvironment to Alleviate Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with high mortality and limited therapeutic options. Dysregulated macrophage polarization drives fibroblast activation and epithelial-mesenchymal transition (EMT), yet no effective management exists. Here, we develop an inhalable methane nanocapsule (MNC) that spatiotemporally controls methane release in the lung to remodel the fibrogenic microenvironment. MNC is formulated via self-assembly of biodegradable poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) and a novel acid-responsive methane prodrug Fe(BPY)2(CH3)2, enhancing mucosal penetration and sustained methane release in acidic inflammatory niches. In a bleomycin (BLM)-induced pulmonary fibrosis model, MNC inhalation achieves efficient lung deposition and sustained methane release, significantly reducing inflammation, ameliorating fibrosis, and improving lung function without systemic side effects. Mechanistically, MNC rebalances macrophage polarization by inhibiting M2 phenotype overexpression and downregulates the MMP9/TIMP-1 ratio to suppress myofibroblast proliferation and EMT, synergistically halting fibrotic progression. This inhalable methane nanocapsule offers a promising strategy for safe and effective IPF treatment.