Galactose‑functionalized DSPE–PEG‑based micelles for targeted delivery of marein: ameliorative effects and mechanisms against methotrexate‑induced acute and chronic liver injury

This is the authors' abstract. We don't add key points for this paper.

Methotrexate (MTX) is widely used in oncology and autoimmune diseases, but dose‑limiting hepatotoxicity restricts its clinical utility. Marein (Mar) exhibits hepatoprotective potential; however, its poor aqueous solubility and limited cellular uptake hinder effective delivery. Hepatocyte‑targeted DSPE–PEG‑based micelles may overcome these limitations. To develop galactose (Gal)-modified DSPE–PEG‑based micelles (Gal@M(Mar)) targeting the asialoglycoprotein receptor (ASGPR) on hepatocytes, and to evaluate their protective effects in acute and chronic MTX‑induced liver injury models. Gal@M(Mar) was prepared and physicochemically characterized. In vitro cellular uptake was assessed in HepG2 cells, and network pharmacology was used to predict involved pathways. In vivo acute and chronic MTX liver injury models were employed to evaluate serum ALT/AST, histopathology, inflammation, apoptosis, and fibrosis markers (α‑SMA, collagen I), using free Mar and M(Mar) as controls. Gal@M(Mar) improved the apparent aqueous dispersibility of Mar, enhanced cellular uptake, and was associated with the modulation of PI3K–Akt/MAPK and inflammatory signaling pathways. Compared with free Mar and M(Mar), Gal@M(Mar) reduced ALT/AST levels, mitigated acute liver injury, as indicated by histopathological, inflammatory, and apoptotic indices, and suppressed chronic fibrosis, as indicated by α-SMA and collagen I expression. Galactose‑functionalized DSPE–PEG‑based micelles facilitated the targeted delivery of Mar to hepatocytes and attenuated MTX-induced acute and chronic liver injury, possibly through the regulation of multiple signaling pathways. These findings support the potential of this nanocarrier-based strategy for the treatment of MTX-associated liver injury.