Dual ligand grafted liposomes for CD44 and CD206 targeted delivery of niclosamide against bisphenol A-induced hepatic fibrosis in albino Wistar rats: In vivo therapeutic efficacy and molecular pathway modulation.

Bisphenol A (BPA) is an endocrine disruptor found in plastics, particularly in food and beverages packaging materials, and can lead to excessive deposition of extracellular matrix. This may result in hepatic fibrosis by activating hepatic stellate cells (HSCs). To address this pathological condition, niclosamide (NIC), an FDA-approved anthelmintic agent, has emerged as a promising antifibrotic compound since it inhibits HSC activation. However, its poor aqueous solubility and availability at the site of action limit its therapeutic application. To overcome this limitation, NIC-loaded hyaluronic acid and mannose-grafted liposomes (NIC-HA-MN-Lipo) were developed to target CD44 on HSCs and CD206-positive mannose receptor M2 macrophages, thereby enabling site-specific delivery to fibrotic liver tissue. In this research, hepatic fibrosis was established in albino rats by oral exposure of BPA (50 mg/kg/day) for a duration of 8 weeks, and treated with free NIC, Placebo-Lipo, non-targeted liposomes (NIC-Lipo), and dual receptor targeted liposomes (NIC-HA-MN-Lipo) for alternative 21-days. After completion of the treatment liver function tests, lipid profiles, oxidative stress parameters (malondialdehyde, protein carbonyl), antioxidant levels (glutathione, catalase, superoxide dismutase), histopathology and scanning electron microscopy (SEM) was performed. Liver fibrosis scoring and immunohistochemically examination of fibrotic indicators (TGF-β1, α-SMA) and receptor expression (CD44, CD206) were also performed. NIC-HA-MN-Lipo-treated animals showed substantial betterment in liver architecture, reduced collagen deposition, and significant normalization of biochemical and oxidative stress markers in comparison to pristine NIC and NIC-Lipo. The dual targeted NIC-HA-MN-Lipo exhibited receptor targeted localization and superior anti-fibrotic efficacy, evidenced by substantial downregulation of α-SMA and TGF-β1. These findings indicate the therapeutic potential of ligand-targeted liposomal delivery of NIC in reversing hepatic fibrosis. NIC-HA-MN-Lipo demonstrated potential antifibrotic effects in BPA-induced liver injury by effectively targeting key fibrogenic cells and modulating the TGF-β-associated pathway in liver fibrosis.