Polymer-lipid hybrid nanoparticles incorporating green coffee extract: enhancing treatment for hepatic steatosis and fibrosis through metabolomic insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30% of adults globally. Its severe form, metabolic dysfunction-associated steatohepatitis (MASH), results in liver damage due to a combination of steatosis and fibrosis. Green coffee extract (GCE) derived from unroasted coffee beans demonstrates therapeutic potential for MASLD/MASH attributed to its rich profile of bioactive compounds. However, challenges remain regarding bioavailability and understanding of mechanisms. In this study, we investigated the bioactive potential of GCE encapsulated in polymer-lipid hybrid nanoparticles (PLNs) as a therapeutic option for MASLD and associated fibrosis. Encapsulation of GCE into PLNs enhanced its physicochemical properties, including reduced particle size (191.5 ± 3.6 nm) and improved polydispersity index (PDI) (0.291), as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) (145.4 ± 26 nm). The encapsulation efficiency (55%) and release kinetics of GCE-PLNs were optimized for sustained bioavailability over 24 h. Metabolomic and chemoinformatic analyses identified 1942 metabolites, including GCE-derived bioactive compounds with structural similarities to therapeutic agents like mesalamine, idebenone, and cysteamine, highlighting potential antifibrotic and hepatoprotective effects. In vitro assays, using HepG2 cells, demonstrated that GCE-PLNs modulate the expression of steatosis- and fibrosis-related genes, such as PLIN1, CPT1A, ACTA2, and COL1A1, in HepG2 and HHSC-N cellular models, suggesting reduced lipid accumulation and fibrotic activity. These findings suggest that GCE-PLNs may represent a promising nanotechnological strategy for the treatment of MASLD.