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Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a \u201ctraffic jam\u2010like\u201d physical obstruction that severely restricts drug penetration and retention. Here, we developed dual\u2010enzyme\u2010modified inhalable nanoparticles (Lipo\/PFD\u2010CB) by co\u2010functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA\u2010approved 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\u2010enzyme 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\u2010induced fibrosis models, Lipo\/PFD\u2010CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme\u2010mediated, microenvironment\u2010remodeling inhalable nanoplatform that effectively \u201cclears the pulmonary traffic jam,\u201d restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.<\/jats:p>","DOI":"10.1002\/adhm.71381","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:03:45Z","timestamp":1782464625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clearing the Pulmonary Traffic Jam With Dual\u2010Enzyme Inhalable Nanoparticles Restore Airflow and Reverse Fibrotic Remodeling"],"prefix":"10.1002","volume":"15","author":[{"given":"Xue\u2010Na","family":"Li","sequence":"first","affiliation":[{"name":"Affiliated Jiangning Hospital of Chinese Medicine China Pharmaceutical University  Nanjing China"},{"name":"College of Pharmacy Yanbian University  Yanji 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