Inhalation-Based Nanoparticle Drug Delivery Targeting the Diseased Lower Airways in Idiopathic Pulmonary Fibrosis

Initiated in the lower airways, idiopathic pulmonary fibrosis (IPF) is a fatal disease that disrupts the lung's functional architecture, for which therapeutics are of limited efficacy; consequently, the disease is progressive and incurable. New therapeutic approaches providing delivery of mechanism-modifying drugs directly to the diseased regions may maximize therapeutic effects while minimizing systemic exposure. In this context, inhalable nanomedicine is an emerging approach for targeted pulmonary delivery, enabling a highly localized therapeutic effect. However, successful clinical translation is hindered by complex biological and engineering challenges in the diseased lungs, including region-specific clearance mechanisms, mucosal airway obstruction, microenvironmental remodeling, and disrupted aerodynamics of particle deposition. This review highlights these critical obstacles in the context of lower airway pathology, focusing on the growing understanding of the epithelial-mesenchymal transition, basal lamina remodeling, and fibroblastic heterogeneity in IPF. Therapeutic payloads, including small molecules, antibodies, and peptides, are compared in terms of stability, targeting, and tissue access. We further discuss emerging nanoparticle-based strategies designed to overcome these pulmonary barriers, with a focus on dendron micelles, dendrimer-peptide conjugates, lipopeptides, and biological vesicles. Finally, we explore advances in formulation engineering and aerosol generation technologies that are shaping the path toward clinically translatable inhalable nanomedicines.