Galactose-decorated lipid nanoparticle-mediated delivery of a selective NLRP3 inhibitor attenuates hepatic inflammation in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic stress-induced hepatic injury closely associated with insulin resistance and genetic predisposition, affecting about 25% of the global population and becoming the leading cause of chronic liver disease. Therapeutic interventions targeting the regulation of inflammation-related pathways have shown potential for significant improvements in MASLD treatment. Herein, we developed galactose-decorated lipid nanoparticles for selective NLRP3 inhibitor targeted liver delivery (MCC950@Gal-LNPs). The galactose modification endowed the LNPs with liver-targeting ability via asialoglycoprotein receptor (ASGPR)-based hepatocellular uptake. The MCC950-loaded formulation effectively reduced the expression of inflammatory regulators and cytokines associated with the NF-κB/NLRP3-related signaling pathway. The Gal-LNPs improved MCC950 accumulation in the liver compared to non-targeted formulations and effectively reduced inflammatory signal activation in vivo. Moreover, MCC950 treatment significantly improved fibrosis by reducing the fibrotic area and normalizing tissue morphology. Therefore, MCC950@Gal-LNPs significantly reduces the inflammatory microenvironment, and MCC950, as a novel NLRP3 inhibitor, appears to be an attractive assay for the effective treatment of NASLD.