Biological barriers and mucus interactions in nanoparticle dry powder inhalation: overcoming the lung defense.

Nanoparticle-based dry powder inhaler (DPI) systems offer a promising platform for the treatment of chronic respiratory diseases by enabling localized delivery, controlled release, and reduced systemic side effects. However, their clinical translation is significantly limited by the lung's complex biological defense mechanisms. Following deposition, inhaled nanoparticles encounter sequential barriers, including the airway mucus layer, pulmonary surfactant interface, epithelial tight junctions, and macrophage-mediated immune clearance. These barriers collectively determine nanoparticle diffusion, retention, cellular uptake, or elimination. Airway mucus, structured by gel-forming mucins such as MUC5AC and MUC5B, forms a viscoelastic hydrogel network that restricts nanoparticle transport through steric hindrance and adhesive interactions. Disease-associated remodeling further increases mucus density and adhesiveness, exacerbating transport limitations. In the alveolar region, hydration-dependent redispersion and rapid adsorption of surfactant components reshape nanoparticle surface properties, influencing colloidal stability and immune recognition. Opsonization by surfactant proteins and recognition by alveolar macrophages often lead to accelerated clearance and inflammatory activation. Optimized nanoparticle design, particularly control of size, surface charge, hydrophilicity, and PEGylation, can enhance mucus penetration, minimize surfactant disruption, and partially evade immune uptake. Formulation strategies such as nano-in-micro architectures improve aerodynamic deposition while protecting nanoscale integrity. Excipients, particle porosity, and device formulation co-design further determine dispersion efficiency and reproducible lung delivery. This review integrates insights from pulmonary biology, immunology, and aerosol engineering to propose a biologically informed framework for DPI development. Addressing both aerodynamic performance and post-deposition biological interactions is essential for achieving sustained pulmonary residence, controlled immune engagement, and improved translational potential of inhaled nanomedicines.