Enzyme-responsive oleoylethanolamide-releasing nanomedicine for sustained liver delivery and therapeutic improvement in early-stage metabolic dysfunction-associated steatohepatitis (MASH).

Transcriptional regulation of lipid metabolism and inflammation through peroxisome proliferator-activated receptor alpha (PPAR-α) has emerged as a promising therapeutic strategy for metabolic dysfunction-associated steatohepatitis (MASH). Oleoylethanolamide (OEA), a potent agonist of PPAR-α, faces limitations due to its hydrophobic nature, rapid enzymatic hydrolysis, and adverse effects. To overcome these issues, we developed a stable polymer micelle-based drug using a self-assembling amphiphilic block copolymer [poly(ethylene glycol)-b-poly(OEA acrylate)] that forms nanostructures (NanoOEA) with diameters in the tens of nanometers in water. Covalently conjugated OEAs in the block copolymer underwent release upon incubation with esterase or liver homogenate. The pharmacokinetic studies of NanoOEA demonstrated the capacity for effective and sustained OEA delivery to the liver. Mice administered NanoOEA intraperitoneally exhibited no observable adverse effects, including locomotor impairment, which was observed in OEA-treated mice receiving an equivalent dose. Intraperitoneal administration of OEA at a dose of 50 mg/kg (body weight) every other day did not yield any discernible effects in mice with early-stage MASH, a condition induced by a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD) for 1 week. On the other hand, NanoOEA treatment demonstrated remarkable efficacy in suppressing the rapid progression of MASH symptoms. This was evidenced by a substantial decrease in plasma aminotransferases and hepatic lipid accumulation, in stark contrast with OEA administration. The hepatic mRNA levels of Ppar-α significantly increased following NanoOEA administration, potentially explaining the enhanced lipolysis and reduced inflammation. NanoOEA, in comparison to direct OEA administration, could provide superior therapeutic effectiveness and safety for early-stage MASH treatment.