Inhaled Angiopoietin‐Like 4 Antisense Oligonucleotide Therapy for Lung Injury and Fibrosis

Abstract Pulmonary infections and fibrosis remain difficult to treat because current interventions target isolated pathways rather than the coupled axes of inflammation, barrier integrity, and tissue remodeling. Here, it is shown that inhalationally delivered, lung‐targeted antisense oligonucleotides against angiopoietin‐like 4 ( Angptl4 ‐ASO) attenuate both infectious and fibrotic lung disease. In murine models of bacterial and viral pneumonia, Angptl4 ‐ASO reduces inflammatory cell infiltration, preserves alveolar architecture, and improves host defence. In bleomycin‐induced fibrosis, treatment lowered Ashcroft scores, collagen deposition, and α‐smooth muscle actin (SMA) expression, indicating broad efficacy across acute and chronic injury. Comparative transcriptomics reveal model‐specific responses, immune and oxidative‐stress programs in pneumonia versus extracellular matrix (ECM)‐remodeling pathways in fibrosis, yet nearly half of all changes converge on a shared ANGPTL4‐regulated network linking hypoxic, inflammatory, apoptotic, and stress response programs. This conserved signature suggests that ANGPTL4 functions as a central regulator of injury resolution regardless of the initiating insult. Mechanistically, Angptl4 ‐ASO reinforced epithelial barrier integrity through coordinated regulation of tight junction and glycoprotein pathways. Longitudinal tracking of a Sulfo‐Cyanine 5 (Cy5)‐conjugated Angptl4 ‐ASO confirmed a lung‐retentive biodistribution, with sustained intrapulmonary localization and minimal systemic dissemination over a 144‐hour window. Collectively, these findings position inhaled ANGPTL4‐ASO as a host‐directed, multi‐axis therapeutic strategy that addresses shared and context‐specific drivers of diverse pulmonary pathologies.