Targeted Sodium Acetate Liposomes for Hepatocytes and Kupffer Cells: An Oral Dual-Targeted Therapeutic Approach for Non-Alcoholic Fatty Liver Disease Alleviation

<b>Background/Objectives:</b> Sodium acetate (NaA) has demonstrated potential in improving non-alcoholic fatty liver disease (NAFLD) by targeting hepatocytes and Kupffer cells. However, its clinical application is hindered by low oral bioavailability and insufficient liver concentrations. Liposomes, with their capacity to encapsulate water-soluble drugs and be surface-modified, offer a promising solution for targeted oral drug delivery. <b>Methods:</b> We designed NaA-loaded liposomes modified with sodium cholate (SC) and mannose (MAN) (NaA@SC/MAN-LPs) to target hepatocytes and Kupffer cells. <b>Results:</b> The NaA@SC/MAN-LPs had a mean diameter of approximately 100 nm with a positive surface charge. Compared to free NaA, NaA@SC/MAN-LPs significantly extended the serum half-life from 2.85 h to 15.58 h, substantially improving in vivo bioavailability. In vivo distribution studies revealed that NaA@SC/MAN-LPs extended the acetate peak time in the liver from 15 min to 60 min and increased hepatic acetate accumulation to 3.75 times that of free NaA. In in vitro cell experiments, NaA@SC/MAN-LPs significantly reduced the lipid droplet, triglycerides (TG), and total cholesterol (TC) in a fatty acid-induced hepatocyte steatosis model and suppressed proinflammation in a lipopolysaccharide (LPS)-activated Kupffer cell inflammation model. Free NaA effectively improved hepatic lipid deposition in NAFLD mice. Furthermore, NaA@SC/MAN-LPs decreased hepatic TG, TC, and the relative area of lipid droplets by 30.44%, 15.26%, and 55.83%, compared to free NaA. Furthermore, the liposomes reduced macrophage infiltration and pro-inflammatory response. <b>Conclusions:</b> The NaA@SC/MAN-LPs demonstrated effective dual targeting effects on hepatocytes and Kupffer cells, significantly improving the pathogenesis of NAFLD, compared to free NaA. This study provides a new strategy for developing effective and safe oral drugs for NAFLD.