Liver-Targeted Gallium-Polyphenol Network by Disrupting the ROS/NETs/PANoptosis Axis for Precision Acute Liver Injury Therapy.

Acute liver injury (ALI), driven by diverse insults such as drug toxicity and ischemia-reperfusion, poses a high mortality risk and lacks targeted therapies. While reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and a coordinated cell death pathway PANoptosis have been implicated, their interplay as a unified pathogenic axis remains elusive. Here, by integrating multi-omics analyses of clinical databases and patient samples, we systematically identified and validated the ROS/NETs/PANoptosis axis as a central driver of hepatocyte damage across multiple ALI etiologies. To therapeutically target this axis, we engineered a liver-targeted gallium-quercetin nanocomposite (Ga@Que) via coordination-driven self-assembly. Ga@Que effectively overcomes the poor bioavailability of natural quercetin. In murine models of acetaminophen-induced and ischemia-reperfusion liver injury, Ga@Que exhibited significant liver accumulation, potently scavenged ROS, suppressed neutrophil infiltration and NETs formation, and attenuated PANoptosis. Consequently, Ga@Que treatment markedly mitigated liver damage and inflammation, outperforming its individual components. Our study not only delineates a novel pathogenic paradigm in ALI but also introduces Ga@Que as a promising precision nanotherapeutic, offering a synergistic and translatable strategy to disrupt this deleterious cascade.