Characterization and Therapeutic Application of Matrix-Bound Nanovesicles in Alcohol-Related Liver Disease.

Alcohol-related liver disease (ALD) is characterized by hepatocellular injury, oxidative stress, inflammation, and extracellular matrix remodeling, yet effective therapies remain limited. Matrix-bound nanovesicles (MBVs) are bioactive vesicles embedded within the extracellular matrix that contribute to tissue repair and immunomodulation, but their role in ALD is unknown. In the current study, hepatic MBVs were isolated from mice subjected to the chronic-plus-binge ethanol model and analyzed using liquid chromatography/tandem mass spectrometry proteomics and pathway enrichment. Ethanol exposure induced marked remodeling of hepatic MBV composition, enriching proteins associated with metabolic stress, detoxification, oxidative phosphorylation, and inflammatory signaling. To investigate therapeutic potential, MBVs derived from healthy porcine urinary bladder matrix were administered to ethanol-exposed mice. MBV treatment reduced plasma alanine aminotransferase and aspartate aminotransferase levels, hepatic triglyceride accumulation, lipid peroxidation, and hepatic expression of oxidative stress-associated genes. Transcriptomic analyses showed that MBV administration partially reversed ethanol-induced pathways associated with oxidative stress, inflammatory signaling, cytokine responses, and metabolic dysfunction. MBV treatment improved hepatocellular injury despite persistent neutrophil-associated inflammatory responses, suggesting selective immunomodulation rather than broad immunosuppression. These findings identify MBVs as disease-responsive components of the hepatic microenvironment during ALD and support a proof-of-concept role for healthy extracellular matrix-derived MBVs as modulators of oxidative stress, metabolic dysfunction, and inflammatory remodeling during alcohol-induced liver injury.