Nanocarrier-Enabled siRNA Therapy for Pulmonary Fibrosis: Pharmacological Rationale, Delivery Barriers, and Translational Opportunities.

Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a progressive interstitial lung disease caused by failed epithelial repair, persistent fibroblast activation, immune dysregulation, and extracellular matrix (ECM) remodeling. Nintedanib and pirfenidone slow functional decline but do not reverse established fibrosis. Small interfering RNA (siRNA) offers sequence-specific silencing of disease-driving genes, but degradation, mucus and ECM barriers, inefficient cellular uptake, and endosomal sequestration restrict its activity in fibrotic lungs. This review examines these barriers alongside the rationale for selecting siRNA targets and nanocarrier platforms. Lipid, polymeric, biomimetic, and inorganic systems are compared in terms of loading, tissue penetration, intracellular release, safety, manufacturing, and clinical feasibility. We also consider single-target and multitarget strategies, pulmonary and systemic administration, disease-model limitations, and early clinical experience. The resulting target-to-delivery framework defines the evidence required before pulmonary siRNA nanomedicines can enter informative clinical testing.