Neutrophil-Mimicking Prussian blue nanozymes for synergistic targeted immuno-metabolic therapy of hepatic ischemia-reperfusion injury.

Liver ischemia-reperfusion injury (IRI), an unavoidable complication during liver resection and transplantation, leads to significant postoperative liver failure and graft dysfunction. This injury is driven by severe oxidative stress, inflammation, and metabolic disruption, with clinical management hindered by the absence of effective multi-target therapies. This study introduces a novel therapeutic platform: neutrophil membrane-coated Prussian blue nanozymes (PBN) delivering metformin (Met@PBN@Neu-CVs). The neutrophil membrane coating enables active targeting of the nanoparticles to the inflamed liver site, enhancing accumulation of the PBN and metformin. Concurrently, neutrophil membrane-coated vesicles (Neu-CVs) adsorb circulating inflammatory cytokines, mitigating inflammation. Crucially, the PBN nanozyme possesses multiple enzyme-mimicking capacities (catalase/CAT, superoxide dismutase/SOD, peroxidase/POD), directly countering oxidative stress. Metformin and PBN act synergistically: they significantly reduce reactive oxygen species (ROS) levels, boost total SOD (T-SOD) activity, elevate the glutathione/oxidized glutathione (GSH/GSSG) ratio (marker of antioxidant capacity), and lower malondialdehyde (MDA) content (marker of lipid peroxidation), collectively suppressing oxidative damage. Following this, mitochondrial membrane potential and structural integrity are restored. Consequently, liver inflammation subsides, evidenced by decreased levels of key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and significantly reduced liver enzyme markers (ALT, AST). Furthermore, Met@PBN@Neu-CVs reprogram liver macrophages, shifting them from the tissue-damaging M1 phenotype to the reparative M2 phenotype, further reducing cytokine release and hepatocyte injury. In summary, treatment with Met@PBN@Neu-CVs concurrently alleviates oxidative stress and inflammation while promoting anti-inflammatory macrophage polarization, effectively protecting against IRI-induced liver damage. This study presents a promising targeted, multi-mechanistic strategy combining antioxidant defense, anti-inflammatory action, metabolic regulation and immune modulation for treating hepatic IRI and enhancing liver repair.