Kim_2025_Adv.Mater__e06373

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, the design of a Lipid droplet inhibitor (LDI) is presented, incorporating porous silica nanostructures along with PKCalpha C1A and Candida Rugosa lipase, aimed at directly degrading lipid droplets. Through its dual-functional design, this nanostructure captures diacylglycerol using PKCalpha 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 reduces lipid droplet formation and triglyceride levels in palmitic acid-treated HepG2 cells. In a high-fat diet-induced MASLD model, it alleviateds 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.