Xanthosomes loaded with recombinant TMEM219 for targeting IGFBP-3: A novel approach for targeted drug delivery to ameliorate liver fibrosis

Abstract

Aims: Insulin-like growth factor binding protein-3 (IGFBP-3) activates hepatic stellate cells, enhancing hepatic fibrogenesis. This research aimed to fabricate IGFBP-3 targeted xanthosomes loaded with transmembraneprotein 219 (TMEM219) to target TGF(3/IGFBP-3 signaling pathway in liver fibrosis. Materials and methods: Recombinant TMEM219 was expressed, purified, and loaded into xanthosomes using thinfilm hydration method. MTT assay performed cytotoxicity on the LX-2 cell line. Liver fibrosis was induced in rats via bile duct ligation, followed by intravenous injection: Sham (SH) and Fibrotic (F) with saline, Short-term (ST) and Long-term (LT) TMEM219 loaded in targeted xanthosomes (0.4 mg/kg), Blank targeted xanthosomes (BST and BLT), and free TMEM219 (Free; 0.4 mg/kg). Evaluations included biochemical parameters, histopathology and immunohistochemistry, a-SMA and COL1A1 mRNA expression, serum IGFBP-3 levels, and TGF-(31 protein expression. Key findings: TMEM219-loaded xanthosomes exhibited a particle size of 149.9 nm, zeta-potential of-11.4 mV, and loading efficiency of 71.5 . MTT assay showed lower cytotoxicity of targeted xanthosomes compared to free TMEM219 (p < 0.05). ST and LT groups significantly improved AST and ALT levels, histopathology (reduced necrosis, fibrogenesis, inflammation), a-SMA and COL1A1 expression, serum IGFBP-3, p-AKT and TGF-(31 expression (p < 0.05, p < 0.01). Significance: Improvements in therapeutic parameters indicated reduced liver fibrosis progression. This study demonstrates that TMEM219-xanthosomes effectively target IGFBP-3, significantly reducing liver fibrosis.