Th e lung has evolved eff ective barriers to prevent the uptake of any inhaled foreign particles [46] . While advantageous in minimizing the potential for uptake of external genetic material (for example, viral DNA), these barriers make it more diffi cult to use gene-based therapies in the lung. Barriers to entry of foreign genetic material into the lung include airway mucus and the epithelial lining fl uid, which traps and clears inhaled material. Th e glycocalyceal barrier hinders contact with the cell membrane, while the tight intercellular epithelial junctions and limited luminal endocytosis further restrict entry of foreign material into the epithelial cells.