Dual-sensitive gelatin-coated chitosan microparticles for targeted semaglutide pulmonary delivery: a novel approach to enhancing anti-inflammatory and anti-fibrotic effects.

This study introduces a novel dual-sensitive drug delivery system, gelatin-coated chitosan microparticles (GL-ChMPs), designed to enhance the lung targeting and therapeutic efficacy of semaglutide (SEM). GL-ChMPs were designed to respond to the acidic environment and metalloproteinases, conditions that are typical in pulmonary fibrosis. SEM-GL-ChMPs exhibited superior lung targeting and prolonged retention while minimizing systemic distribution. SEM-GL-ChMPs demonstrated 21-fold and 2-fold higher time-averaged lung drug exposure compared to free SEM solution and uncoated ChMPs, respectively. In a bleomycin-induced chronic lung injury model, SEM-GL-ChMPs effectively attenuated inflammation and fibrotic progression in lung tissues. On the inflammatory front, SEM-GL-ChMPs significantly reduced immune cell infiltration, which was accompanied by lower BALF total protein and LDH, suggesting reduced alveolar-capillary barrier disruption and cellular injury. At the molecular level, there was a marked inhibition of TLR4/NFκB signaling and a downregulation of pro-inflammatory cytokines TNF-α, IL-6, and IL-8. On the fibrotic side, SEM-GL-ChMPs resulted in a pronounced decrease in key fibrogenic mediators, including TGF-β1 and p-SMAD3, and critical markers like α-SMA and Col1a1. Histopathological analysis further reinforced these findings. The gelatin coating was designed to exploit MMP-2 overexpression in fibrotic lungs, enabling localized drug release. Our data confirmed that metalloproteinases are positively correlated with fibrosis progression, supporting the rationale for this enzyme-responsive delivery approach. Collectively, SEM-GL-ChMPs not only improved lung-specific drug delivery and retention but also effectively mitigated the hallmarks of chronic lung injury at cellular, molecular, and tissue levels. This underscores their promise as a precision-targeted, dual-sensitive platform for managing chronic inflammatory and fibrotic lung diseases.