Local delivery of therapeutic nanoparticles to the lung is an ideal method for treating various lung diseases, due to the simple, non-invasive administration (inhalation) and direct access to the affected tissues. However, the respiratory tract has highly efficient mechanisms for rapidly removing deposited particles. The inner surfaces of the lung airways are coated with a highly adhesive, viscoelastic mucus layer, which is continuously, rapidly cleared from the lungs to the GI tract via the pharynx by cilia that line the airway epithelium. Our research efforts in the lung are focused on overcoming this barrier to efficiently deliver therapeutic (gene and drug loaded) nanoparticles that experience prolonged residence time in the lungs and continuously release therapeutics. In this vein, we are working to formulate biodegradable, therapeutic-loaded mucus-penetrating particles (MPP) for more efficient treatment of lung diseases. For example, ongoing work in our lab is focused on formulation and optimization of gene-loaded MPP for CF gene therapy. Despite the discovery of the CFTR gene more than two decades ago, effective gene delivery has not been realized in clinical trials to date. One potential reason is rapid, efficient clearance of particles trapped in the mucus by the mucociliary escalator. Indeed, we previously found that clinically tested viral and non-viral gene carriers were extensively hindered in human CF sputum. Recently, we have formulated MPP gene carriers that rapidly penetrate human CF sputum. Application of these particles in mice led to more uniform distribution of the particles in the lung, increased retention in the lung, and increased transfection of a reporter gene in the lung. This data suggests that MPP gene carriers may provide a promising new platform for treatment of CF and other lung diseases. We are currently working on similar strategies to improve drug delivery for various lung diseases, including lung cancer and COPD.