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 a high mortality rate and limited therapeutic options. Dysregulated macrophage polarization as a driver of fibroblast activation and epithelial-mesenchymal transition (EMT) is the key to IPF evolution, but lacks an effective management approach. Herein, we develop a novel inhalable methane nanocapsule (MNC) which is able to spatiotemporally control methane release in the lung to locally remodel fibrogenic microenvironment in IPF. MNC is formulated through self-assembly of biodegradable poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) copolymer and a new acid-responsive methane prodrug Fe(BPY)2(CH3)2 to enhance the efficacy of pulmonary methane delivery by facilitating mucosal penetration and sustained methane release in response to the acidic inflammatory niche. In a bleomycin (BLM)-induced pulmonary fibrosis model, MNC inhalation achieves efficient MNC deposition and sustained methane release in the lung, significantly reducing inflammation progression, ameliorating fibrosis formation, and improving lung function without systemic side effects. Mechanistically, MNC not only rebalances macrophage polarization by inhibiting M2 phenotype overexpression but also downregulates the ratio of MMP9/TIMP-1 to suppress myofibroblast proliferation and EMT, synergistically suspending the fibrotic progression of IPF. The developed inhalable methane nanocapsule offers a promising strategy to remodel pulmonary fibrogenic microenvironment for safe and effective treatment of IPF.