Inhaled collagenase I liposomes reverse pulmonary fibrosis via local collagen degradation

Pulmonary fibrosis (PF) involves excessive collagen deposition and mucus buildup, which not only impairs oxygen supply but also hinders the efficient delivery of therapeutic drugs. Collagenase I can specifically degrade collagen though its current formulation, i.e. , a local injection, cannot reach the lung. Here, we develop collagenase I-loaded liposomes (CLP) for the inhalation therapy of PF. CLP was prepared by reverse-phase evaporation, owning nearly complete drug encapsulation, a small average size (66.45 nm), high enzyme activity (102.29 U/mL), the appropriate aerodynamic diameter (3.79 μm), and high lung deposition (fine particle fraction, 52.42%). Unlike collagenase I solutions (CS), CLP rapidly penetrated through the thick simulated lung mucus. CLP suppressed the growth of MRC-5 fibroblasts without influence on BEAS-2B epithelial cells. CLP specifically degraded the collagen in the excised pulmonary fibrotic tissues without significant harm to normal lung tissues. In bleomycin-induced PF mouse models, the intratracheal administration of CLP remarkably normalized the lung tissue architecture, motor behavior, and pulmonary function, and importantly, increased survival rates. The typical fibrosis markers (Col I, Col III, α -SMA, FN, collagen area fraction), proinflammatory cytokines and immune-related factors decreased with collagen clearance. Inhaled CLP can reverse PF by highly efficient fibrotic tissue penetration and local collagen degradation.