Lipid Droplet Inhibitors for Disrupting Lipid Accumulation in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Excessive lipid droplet accumulation in hepatocytes drives the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), often leading to inflammation and fibrosis. As obesity and metabolic syndrome rise, MASLD has become a global concern, spurring research into effective treatments. Here, we present the design of a Lipid droplet inhibitor (LDI), incorporating ultra-large mesoporous silica nanostructures along with PKCα C1A and Candida Rugosa lipase, aimed at directly degrading lipid droplets. Through its dual-functional design, this nanostructure captures diacylglycerol using PKCα C1A while hydrolyzing triacylglycerol into smaller molecular fragments via the lipase. Notably, the amphiphilic biomolecules in LDI facilitate the formation of a Pickering emulsion, ensuring stable localization at the lipid-water interface for efficient interaction with lipid droplets. LDI reduced lipid droplet formation and growth in HepG2 cells. In a high-fat diet-induced MASLD model, it alleviated liver pathology and, lowered injury scores by up to 84%. Furthermore, lipidomic analysis confirmed that LDI effectively modulated the hepatic lipid profile, suggesting its potential as a nanoplatform for counteracting lipid droplet accumulation.