Dual-mechanism inhalable nanocomposite restores the alveolar mucus barrier and enables deep-lesion delivery for synergistic treatment of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition, epithelial barrier failure, and pathological remodelling of the alveolar mucus layer, which together limit the effectiveness of inhaled therapeutics. Here, we report a dual-mechanism inhalable system, CL-Shell/PF-µGel, designed to restore the dysfunctional mucus barrier while delivering antifibrotic agents into deep fibrotic lesions. The platform integrates calcium phosphate-shell coated celastrol-loaded liposomes (CL-Shell) with pirfenidone-loaded gelatin microgels (PF-µGel). The calcium phosphate shell is generated through a layer-by-layer mineralization process that produces a stable, uniformly charged coating capable of traversing diseased mucus and protecting the liposomal core from enzymatic degradation, thereby enabling efficient intracellular delivery of celastrol to activated myofibroblasts. Concurrently, microscale PF-µGels (1-5 μm) deposit along airway and alveolar surfaces, regulate local hydration to normalize abnormal mucus rheology, and release pirfenidone in a sustained manner to support epithelial repair and suppress profibrotic signalling. In vitro and in vivo studies revealed that CL-Shell/PF-µGel enhances pulmonary retention and attenuates fibroblast activation. This work establishes a biomimetic inhalation strategy that couples barrier repair with targeted deep-lesion therapy, offering a promising and clinically translatable approach for IPF and other chronic respiratory diseases.