Self-assembled PEGylated nanoparticles based on Elafibranor derivative 3d for the treatment of metabolic dysfunction-associated steatohepatitis

Treatment of metabolic dysfunction-associated steatohepatitis (MASH) is constrained by the challenge of delivering highly hydrophobic drugs, whose poor water solubility severely hinders clinical application. A prodrug-based self-assembly strategy was employed. PEGylated 3d was synthesized via covalent conjugation of Elafibranor derivative 3d with Polyethylene glycol (PEG), and the amphiphilic conjugate spontaneously self-assembled into nanoparticles in aqueous solution without requiring exogenous polymers/lipids. The nanoparticles were characterized for size, morphology, and colloidal stability. In vitro lipid-lowering activity was assessed in an Free fatty acids (FFAs) -induced HepG2 model. In vivo efficacy was evaluated in a high-fat diet (HFD)-induced MASH mouse model following oral administration of PEGylated 3d nanoparticles (30 mg/kg, 3d-equivalent) compared to free 3d. PEGylated 3d self-assembled into stable spherical nanoparticles with a mean diameter of 255.3 ± 24.79 nm. In the MASH mouse model, PEGylated 3d (30 mg/kg) demonstrated significantly superior efficacy compared to free 3d: serum total cholesterol (TC) decreased by 34.3%, liver superoxide dismutase (SOD) activity increased by 35.6%, non-alcoholic fatty liver disease (NAFLD) activity score (NAS) score decreased by 62.3%, and liver lipid droplets reduced by 90.2%. The structure-guided PEGylated prodrug nanoassembly effectively overcomes the solubility limitation of hydrophobic MASH therapeutics and exhibits enhanced anti-steatotic and antioxidant effects through improved drug delivery. This work establishes a promising nanocarrier-free drug self-delivery paradigm for MASH treatment. The PEGylated nanoassembly of Elafibranor derivative 3d significantly enhances aqueous solubility and maintains colloidal stability for > 10 days. In vitro, it reduces lipid accumulation in FFAs-induced HepG2 cells; in vivo, it outperforms free 3d in a MASH mouse model, reducing serum cholesterol by 34.3% and liver lipid content by 90.2%. This self-assembled nanomedicine offers a potent strategy for hydrophobic MASH therapeutics.