Dual-targeting galactose-functionalized hyaluronic acid modified lipid nanoparticles delivering silybin for alleviating alcoholic liver injury.

Alcoholic liver injury stands as a predominant pathogenic contributor to the global burden of liver diseases, with alcohol consumption serving as a significant determinant of worldwide morbidity and mortality. Given that liver-targeted therapy for mitigating alcoholic liver injury remains to be a major clinical challenge due to the poor specificity and instability associated with single targeting modification in actively targeted nanomedicine systems, bifunctional targeting modification may serve as a more promising strategy. Here, galactose-functionalized hyaluronic acid (Gal-HA) coated cationic solid lipid nanoparticles carrying silybin (Gal-HA/SIL-SLNPs) featuring dual-targeting hyaluronic acid (HA) and galactose (Gal) moieties, enabled specific liver surface targeting of asialoglycoprotein receptor (ASGPR) and cluster of differentiation 44 (CD44) proteins to enhance silybin uptake, while simultaneously ameliorating the deficiencies of positively charged lipid nanoparticles as drug carriers and preserving their stability in the bloodstream. Based on the findings, Gal-HA/SIL-SLNPs with excellent biocompatibility demonstrated improved cellular internalization and liver distribution, while also displaying ideal curative properties in a mouse model of alcohol-induced liver injury without causing damage to other organs. This work suggests that Gal-HA/SIL-SLNPs with dual modification may represent an encouraging approach for developing more effective liver targeted nano-drug delivery systems to achieve accurate medication for alcoholic liver injury.