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

Abstract 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. EV neo (neonatal rat liver‐derived extracellular vesicle) and EV adult (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 EV neo vs EV adult . 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 EV neo ‐specific enrichment of mitochondrial biogenesis, anti‐inflammatory, and anti‐apoptotic pathways. EV neo 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 EV neo ’s superior therapeutic efficacy over EV adult , 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.