Abstract
Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by high mortality rates and limited therapeutic options. Although Asiaticoside (AS) exhibits potent anti-fibrotic activity, its clinical potential is hindered by low bioavailability and insufficient pulmonary targeting. Methods: In this study, pH-responsive and charge-tunable AS-loaded liposomes were prepared using the thin-film hydration method and subsequently optimized. The liposomes were characterized in terms of their physicochemical properties, pH-triggered release, stability, and mucus-penetrating capability. Furthermore, cellular uptake by MH-S cells, in vivo biodistribution, and the anti-fibrotic efficacy and safety were evaluated in a bleomycin-induced PF mouse model following pulmonary administration. Results: The optimized DPPC-based liposomes exhibited high encapsulation efficiency, excellent stability, pH-dependent drug release, and enhanced mucus penetration with reduced macrophage uptake. These liposomes significantly inhibited fibroblast activation in vitro and attenuated lung injury, collagen deposition, and inflammatory cytokine levels in vivo, demonstrating superior therapeutic efficacy compared to free AS, coupled with a favorable biosafety profile. Conclusions: This optimized pH-responsive, pulmonary-targeted liposomal system remarkably enhances the anti-fibrotic efficacy of AS and represents a promising nanodelivery strategy for the treatment of PF.