Abstract

To address the intertwined pathologies of oxidative stress, immune dysregulation, and lipid metabolic disorders in acute liver injury (ALI), we engineered an innovative nanosystem: M2@SAM-F21. M2@SAM-F21 features an M2 macrophage membrane coating encapsulating diselenide-bridged mesoporous silica nanoparticles for silymarin and FGF21 plasmid DNA codelivery, enabling synergistic multidimensional treatment. First, reactive oxygen species (ROS)-responsive oxidative stress is mitigated. Diselenide bonds undergo ROS-triggered cleavage, achieving precise silymarin release that efficiently scavenges multiple ROS types, significantly mitigating hepatic oxidative damage. Simultaneously, FGF21 drives immune reprogramming. Efficiently expressed FGF21 protein drives macrophage polarization toward the M2 anti-inflammatory phenotype, effectively reducing proinflammatory cytokine levels, with TNF- α decreased to 61 pg/mL and IL-6 reduced to 20 pg/mL, while increasing IL-10 to 68 pg/mL to reverse the immune microenvironment imbalance. In addition, metabolic homeostasis is restored. Activated fatty acid oxidation pathways substantially decrease serum concentrations of total cholesterol (TC) to 4.984 mmol/L and triglycerides (TG) to 0.586 mmol/L, and almost reduce hepatocellular lipid droplet accumulation by 76%, resolving metabolic dysregulation. In both alcoholic and drug-induced ALI models, M2@SAM-F21 demonstrates exceptional hepatoprotection. For example, it significantly restores serum alanine aminotransferase (ALT) to 46.6 U/L and aminotransferase (AST) to 180 U/L in the alcoholic ALI model, while markedly alleviating histopathological vacuolization and steatosis, with biological distribution imaging confirming inflammation-targeted accumulation and proteomic analysis further elucidating therapeutic mechanisms. Exhibiting superior biosafety and dual therapeutic-prophylactic pote