Targeted delivery of empagliflozin via glycyrrhetinic-acid-modified lipid nanoparticles for metabolic dysfunction–associated steatotic liver disease therapy

• Glycyrrhetinic-acid-modified lipid nanoparticles achieved 89 % encapsulation efficiency and roughly tripled the cellular uptake of empagliflozin by human hepatocytes in vitro. • The targeted formulation lowered intracellular lipid droplets and normalised the expression of sterol regulatory element binding protein-1c, fatty acid synthase, and sirtuin-1 in free-fatty-acid-challenged LO2 liver cells. • In a high-fat diet–induced hepatic steatosis mouse model relevant to metabolic dysfunction–associated steatotic liver disease (MASLD), the formulation restored serum triglyceride, total cholesterol, low-density- and high-density-lipoprotein cholesterol toward normal values and markedly relieved hepatic steatosis. • Treatment reduced circulating interleukin-6, interleukin-1β, and tumour necrosis factor-α, improved oral glucose tolerance and insulin tolerance test outcomes, and lowered the homeostatic model assessment of insulin-resistance index. • The delivery system provided sustained drug release, caused less than 5 % haemolysis, and produced no histological or biochemical toxicity in major organs, demonstrating excellent biosafety. Metabolic dysfunction–associated steatotic liver disease (MASLD) is a common metabolic disorder characterized by excessive lipid accumulation in the liver, insulin resistance, and impaired glucose metabolism. Empagliflozin (EGZ) effectively reduces liver fat, enhances insulin sensitivity, and improves glucose metabolism in various metabolic conditions. To specifically target hepatocytes, glycyrrhetinic acid (GA) was incorporated into lipid nanoparticles (LNPs), creating a GA-targeted EGZ@LNP-GA drug delivery system designed to enhance the therapeutic effects of EGZ on MASLD. The EGZ@LNP-GA formulation was thoroughly characterized by evaluating particle size, encapsulation efficiency, and in vitro release kinetics. In vitro studies showed that EGZ@LNP-GA exhibited high specificity for LO2 cells compared to HeLa and HUVEC cells. Treating LO2 cells with EGZ@LNP-GA diminished lipid accumulation, as demonstrated by Oil Red O staining and triglyceride (TG) content assays. Western blot analysis revealed that EGZ@LNP-GA downregulated lipogenic factors SREBP1c and FAS, while upregulating the lipid oxidation regulator SIRT1, indicating its potential to enhance lipid metabolism. In an HFD-induced steatosis model, EGZ@LNP-GA reduced hepatic lipid accumulation, lowered inflammatory cytokines, improved insulin sensitivity, and enhanced glucose metabolism. These findings support the GA-targeted EGZ@LNP-GA system as a promising strategy for MASLD-related metabolic dysfunction.