LDI, A Lipid Droplet Inhibitor, Disrupts Lipid Accumulation and Modulates Hepatic Lipid Profiles in Fatty Liver

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 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 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.