Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.