pPB peptide-modified nanostructured lipid carriers loaded with astragaloside IV as a potential strategy for enhanced antifibrosis therapy

Activated hepatic stellate cells (HSCs) are central to hepatic fibrosis pathogenesis, driving excessive extracellular matrix deposition and pathological angiogenesis. Despite their therapeutic potential, conventional antifibrotic agents face challenges in selectively targeting HSCs, limiting efficacy and increasing off-target toxicity. Here, we address this limitation by leveraging the overexpression of platelet-derived growth factor receptor-beta (PDGFR-β) on activated HSCs to develop pPB/AST NLCs, a nanostructured lipid carriers (NLCs) system conjugated with the PDGFR-β-targeting pPB peptide for delivery of astragaloside IV (AST). Cellular uptake studies in TGF-β1-activated HSCs revealed a significant increase for pPB peptide-mediated NLCs compared to non-targeted NLCs, with co-localization analysis confirming PDGFR-β-dependent internalization. In vivo imaging further confirmed selective hepatic accumulation and prolonged retention of pPB peptide-mediated NLCs, without cytotoxicity or systemic toxicity. pPB/AST NLCs enabled selective accumulation in fibrotic livers, achieving superior efficacy in mitigating hepatic fibrosis by attenuating Collagen deposition, reducing liver-to-body weight ratios, and suppressing hepatocellular injury biomarkers through PDGFR-β-targeted engagement on activated HSCs. Histopathological improvements included diminished fibrotic progression, Collagen accumulation, and inflammatory cell infiltration, accompanied by significant reductions in pro-fibrotic markers and pro-inflammatory cytokines. Quantitative decreases in hepatic hydroxyproline and α-SMA levels corroborated attenuated injury, while suppression of pathological angiogenesis highlighted additional therapeutic benefits.

Astragaloside IV; Hepatic stellate cells; Liver fibrosis; Nanostructured lipid carrier; PDGFR-β.