Rational adjustment of surface physicochemical properties of inhalable nanocarriers significantly influences their in vivo fate during pulmonary delivery. Among these, surface hydrophilicity/hydrophobicity has been recognized as a critical factor in the transmucosal process. However, the impacts of surface hydrophilicity/hydrophobicity on the transcellular performance and ultimate therapeutic effects of pulmonary-delivered nanosystems still remain unelucidated. In this study, we developed a series of liposomes with varying surface hydrophilicity to investigate the effect of surface properties on both local and systemic drug delivery. Interestingly, low-hydrophilic liposomes exhibited enhanced systemic absorption, whereas high-hydrophilic liposomes demonstrated prolonged pulmonary residence after inhalation. To validate this principle, we applied two disease models. In a type II diabetes mellitus model, low hydrophilic liposomes loaded with GLP-1 receptor agonists (Liraglutide or Semaglutide) showed excellent systemic drug delivery and hypoglycemic effects. In an OVA-induced allergic asthma model, budesonide-loaded high hydrophilic liposomes significantly alleviated symptoms while reducing dosing frequency. Mechanistic studies further revealed that liposomes with lower surface hydrophilicity could enhance the transcellular transport efficiency of the drug through alveolar epithelial cells, while those with higher surface hydrophilicity prolonged the pulmonary residence of the drug by decreasing alveolar epithelium transportation and the avoidance of macrophage clearance. Lastly, we evaluated the biocompatibility of these liposomes following inhalation. Overall, tuning the surface hydrophilicity/hydrophobicity of inhalable nanocarriers to suit local or systemic delivery goals offers valuable insights for the rational design of advanced pulmonary delivery systems.
