Clearing the Pulmonary Traffic Jam With Dual-Enzyme Inhalable Nanoparticles Restore Airflow and Reverse Fibrotic Remodeling.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disorder marked by aberrant mucus hypersecretion and excessive extracellular matrix (ECM) deposition, which together severely limit the effectiveness of current therapies. Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a "traffic jam-like" physical obstruction that severely restricts drug penetration and retention. Here, we developed dual-enzyme-modified inhalable nanoparticles (Lipo/PFD-CB) by co-functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA-approved antifibrotic drug pirfenidone (PFD). Specifically, bromelain cleaves mucin crosslinks to reduce mucus viscosity, while collagenase degrades dense ECM fibers to facilitate deep tissue penetration and prolonged retention. This dual-enzyme remodeling strategy significantly improved aerosol deposition efficiency (86.5%) and optimized the pharmacokinetic profile and tissue distribution of PFD. In both early and advanced bleomycin-induced fibrosis models, Lipo/PFD-CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme-mediated, microenvironment-remodeling inhalable nanoplatform that effectively "clears the pulmonary traffic jam," restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.