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

Background & Aims: Alcohol-related liver disease (ALD) lacks effective therapies, and understanding extracellular matrix (ECM) remodeling during disease progression may reveal novel therapeutic targets. Matrix-bound nanovesicles (MBVs), embedded within ECM, contain bioactive proteins and microRNAs and promote tissue repair in various injury models. However, MBVs remain unexplored in ALD. In the present study, we not only characterized how alcohol alters hepatic MBV composition, but also evaluated therapeutic effects of exogenous healthy MBVs in alcohol-induced liver injury. Approach: Using the NIAAA chronic-plus-binge ethanol model, we first isolated hepatic MBVs and performed LC-MS/MS proteomic analysis with pathway enrichment to define alcohol-induced cargo alterations. We then administered MBVs from healthy porcine urinary bladder matrix to ethanol-exposed mice and assessed therapeutic effects through histopathological evaluation and bulk RNA sequencing. Results and Conclusions: Ethanol exposure enriched hepatic MBVs for metabolic stress and detoxification proteins, indicating disease-associated cargo remodeling. Therapeutic administration of healthy MBVs reduced steatosis, lipid peroxidation, and fibrogenic gene expression while normalizing ethanol-induced transcriptional programs related to oxidative stress, inflammation, and metabolism. MBVs acted context-dependently. That is, they promoted mild ECM remodeling in healthy livers while attenuating pathological signaling in injured tissue, suggesting they stabilize hepatocyte homeostasis rather than directly suppressing immunity. These findings establish MBVs as both disease-responsive biomarkers and therapeutic modulators of the hepatic microenvironment in ALD.