Neonatal Liver‐Derived Extracellular Vesicle: Unlocking Mitochondrial Repair and Regenerative Mechanisms in Alcoholic Liver Disease

Alcoholic liver disease (ALD) represents a formidable global health challenge with limited effective therapeutic interventions. This study investigates the therapeutic potential and underlying mechanisms of xenogeneic neonatal liver-derived extracellular vesicles in ALD. EVneo (neonatal rat liver-derived extracellular vesicle) and EVadult (adult rat liver-derived extracellular vesicle) are isolated via differential centrifugation and rigorously characterized. A preclinical ALD mouse model is established using the National Institute on Alcohol Abuse and Alcoholism model, with comparative therapeutic assessment of intravenously administered EVneo vs EVadult. Proteomic profiling of liver tissues and EVs （extracellular vesicles）, integrated with immunohistochemical analyses, fluorescence imaging, mitochondrial functional assays, and quantification of inflammatory/regenerative markers, elucidated therapeutic mechanisms. Key findings demonstrate that EVneo-specific enrichment of mitochondrial biogenesis, anti-inflammatory, and anti-apoptotic pathways. EVneo administration significantly attenuates hepatic steatosis and inflammatory responses, restores mitochondrial homeostasis through redox balance modulation, induces macrophage polarization toward an M2 reparative phenotype, enhances hepatocyte proliferation, and suppresses apoptotic signaling. Comparative analysis revealed EVneo 's superior therapeutic efficacy over EVadult, attributable to its developmentally programmed cargo that orchestrates mitochondrial resilience, immunometabolic reprogramming, and parenchymal regeneration. These findings establish developmental stage-specific EV therapeutics as a paradigm for ALD treatment, emphasizing their multimodal mechanistic advantages in counteracting alcohol-induced hepatopathology.