Mucus is the most frequently cited extracellular barrier to the delivery of genes to the cells of the upper respiratory tract [120,135]. Kitson et al. found a 25-fold increase in transfection efficiencies with lipoplexes in mucus-depleted tissues compared to those that were mucus covered [136]. Respiratory mucus lines the luminal side of the tracheobronchial tree from the entrance of the trachea to the terminal bronchioles, humidifying inspired air and trapping small particles and microorganisms until they can be transported out of the lungs. The continuous flow of dry air into the lungs dehydrates mucus at the air-liquid interface, forcing mucus to partition into two layers: a viscous superficial "gel" layer (0.5-2.0 mm) covering an aqueous periciliary "sol" layer (7-10 mm) [132]. Inhaled particles that become trapped in the mucus gel layer are removed by mucociliary transport [132]. Beating cilia extending from the mucus sol layer sweep the mucus gel layer from the lungs into the pharynx. The continual motion of cilia at the interface of the sol and gel layers creates a slippage plane, which aids in clearing mucus and maintaining an unstirred gel layer [120,132].

An improved understanding of the relationship between mucus properties and particle transport is critical to the design of DNA carriers for delivery in the nondistal airways of the lung. Important properties of the mucus gel layer, including viscosity, elasticity, adhesivity, permeability, and clearance rate, can be affected by disease, inflammation, bacterial infection, and the addition of chemical substances [120,137-139]. For example, cystic fibrosis (CF) is a genetic disease characterized by reduced clearance of thick airway secretions. Mucus from cystic fibrosis patients is denser and more highly glycosylated than in normal patients [138]. The addition of chemical agents (including polylysine salts, surfactants, and DNase) can reduce the viscosity of CF mucus, thereby increasing the clearance rate of airway secretions [140]. DNA vector design should, therefore, be guided by the nature and functionality of airway mucus in the relevant disease state [138]. For example, in cases where the mucosal layer is a rate-limiting step to gene delivery, the addition of adjuvants that decrease the viscosity of mucus may increase gene transfer to airway epithelial cells [88].

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