PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States; there is no curative treatment. Both genetic and biomarker surveys strongly implicate dysregulated TGF-β signaling as a contributor to COPD development and progression. Excessive TGF-β signaling results in airway obstruction caused by epithelial thickening and alveolar epithelial cell apoptosis with airspace simplification, each of which is observed in mouse models and patients with COPD. We recently showed that TGF-β antagonism with systemic angiotensin receptor blockers (ARB) protected against pulmonary damage in mice exposed to chronic cigarette smoke (CS) and reversed airspace enlargement in a transgenic mouse model of emphysema. ARB administered orally provides very little drug delivery to the lungs and also cause significant systemic side effects. Thus, we have focused on the development of ARB formulations that could be delivered directly to the lung via inhalation by nebulization. Our pilot data suggests that local administration of an ARB compound, formulated in a novel “mucus-penetrating particle nanocrystal” (MPP-NC) for inhalation, provides significantly enhanced lung drug levels (compared to a conventional oral formulation) and effective TGF-β antagonism, resulting in protection against TGF-β-mediated lung injury. Of note, the ARB MPP-NC formulations are composed entirely of materials that are generally regarded as safe, thereby making our approach potentially highly translational. We also introduce an elegantly simple approach to maximize lung distribution and retention of inhaled therapeutics, namely hypo-osmolar vehicle solutions. We plan to develop MPP-NC formulations with eight potent FDA-approved ARB drugs and thoroughly characterize in vitro, followed by screening of promising formulations for TGF-β antagonism in an acute CS-exposed mouse model of lung injury. The most promising formulations delivered in an optimized hypo-osmolar vehicle solution will be tested for pharmacokinetics, safety, and therapeutic efficacy following repeated local administration in a chronic CS-exposed mouse model of COPD.