The human respiratory system contains a complex network of anatomical, physiological, and biochemical barriers that have a substantial impact on the efficacy of pulmonary drug delivery. This chapter concentrates on three essential barriers: the lung mucus barrier, the surfactant layer, and the presence of highly expressed proteins, such as Club Cell Secretory Protein (CC16), in the airway lining fluid. The surfactant layer, which is critical for decreasing alveolar surface tension and regulating lung function, can interact with inhaled formulations, influencing drug deposition and distribution. Drug bioavailability in the lungs is further modulated by proteins like CC16, which can bind to hydrophobic molecules. Innovative approaches to overcoming these obstacles are presented, including the development of mucus-penetrating particles, surfactant-compatible carriers, and customized formulations that reduce protein-drug interactions. By overcoming these limitations, pulmonary drug delivery can be improved, leading to more effective means of treating various types of respiratory disorders.
