Morphology-driven zinc oxide biointeractive carriers with biological barrier modulating effects for pulmonary delivery of liraglutide

Pulmonary delivery provides a noninvasive route for systemic administration of biologics, yet efficient lung deposition and permeation across pulmonary barriers remain major challenges. In this study, morphology-engineered zinc oxide (ZO) biointeractive carriers were fabricated and evaluated as inhalable carriers for liraglutide (LG). Three distinct morphologies were obtained: smooth spherical ZO-1 (5-7 μm), spiky sea-urchin-like ZO-2 (5-8 μm with elongated ~ 3.5 μm tips), and compact spiky ZO-3 (1-3 μm with short ~ 1.3 μm tips). Particle image velocimetry (PIV) revealed morphology-dependent aerodynamic behaviors, where ZO-3 exhibited turbulence-driven dispersion favoring distal lung deposition. At the cellular level, ZO-3 demonstrated enhanced mucus penetration and reduced macrophage uptake, maintaining prolonged contact with the epithelial surface. Following intratracheal administration, LG@ZO-3 achieved bioavailability of ~ 60% relative to subcutaneous injection in healthy rats and ~ 51% in diabetic rats, far exceeding the < 2% oral bioavailability of semaglutide. These results suggest that morphology-controlled modulation of aerodynamic and biological interactions can overcome multiple pulmonary barriers, offering a promising strategy for effective inhalable delivery of peptide therapeutics.