Oral delivery of chitosan-bilirubin nanoparticles alleviates hepatic inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe chronic liver disease that often leads to complications, such as cirrhosis and hepatocellular carcinoma. Despite intensive research and development efforts, there are relatively few approved therapeutics for MASH. Here, we report an oral nanomedicine comprising bilirubin-conjugated low molecular weight water-soluble chitosan (designated LMWC-BRNPs) that can alleviate oxidative stress and lipogenesis in liver to treat MASH in a mouse model. Upon oral administration, LMWC-BRNPs were readily absorbed and reached the liver in a mouse model of MASH generated using a methionine and choline-deficient (MCD) diet. Orally administered LMWC-BRNPs were primarily taken up by liver macrophages and hepatic stellate cells (HSCs) and could modulate dysregulated hepatic immunity to alleviate inflammation in the livers of MASH mice. Orally administered LMWC-BRNPs also prevented uncontrolled fat deposition by activating peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes, and thereby reduced fibrosis. These findings suggest that our bilirubin-based nanomedicine, which has a unique action mode and potent therapeutic efficacy, has the potential to be translated as an oral therapeutic for treating MASH in patients.