Integrated cascade antioxidant nanozymes-Cu_5.4O@CNDs combat acute liver injury by regulating retinol metabolism

<b>Background:</b> Acute liver failure (ALF) represents a critical medical condition marked by the abrupt onset of hepatocyte damage, commonly induced by etiological factors such as hepatic ischemia/reperfusion injury (HIRI) and drug-induced hepatotoxicity. Across various types of liver injury, oxidative stress, heightened inflammatory responses, and dysregulated hepatic retinol metabolism are pivotal contributors, particularly in the context of excessive reactive oxygen species (ROS). <b>Methods:</b> C-dots were combined with Cu_5.4O USNPs to synthesize a cost-effective nanozyme, Cu_5.4O@CNDs, which mimics the activity of cascade enzymes. The <i>in vitro</i> evaluation demonstrated the ROS scavenging and anti-inflammatory capacity of Cu_5.4O@CNDs. The therapeutic potential of Cu_5.4O@CNDs was evaluated <i>in vivo</i> using mouse models of hepatic ischemia/reperfusion injury and LPS/D-GalN induced hepatitis, with transcriptome analysis conducted to clarify the mechanism underlying hepatoprotection. <b>Results:</b> The Cu_5.4O@CNDs demonstrated superoxide dismutase (SOD) and catalase (CAT) enzyme activities, as well as hydroxyl radical (·OH) scavenging capabilities, effectively mitigating ROS <i>in vitro</i>. Furthermore, the Cu_5.4O@CNDs exhibited remarkable targeting efficacy towards inflammation cells induced by H₂O₂ and hepatic tissues in murine models of hepatitis, alongside exhibiting favorable biocompatibility in both <i>in vitro</i> and <i>in vivo</i> settings. Moreover, it has been demonstrated that Cu_5.4O@CNDs effectively scavenged ROS, thereby enhancing cell survival <i>in vitro</i>. Additionally, Cu_5.4O@CNDs exhibited significant therapeutic efficacy in mice models of HIRI and lipopolysaccharide-induced acute lung injury (LPS-ALI). This efficacy was achieved through the modulation of the ROS response and hepatic inflammatory network, as well as the amelioration of disruptions in hepatic retinol metabolism. <b>Conclusions:</b> In summary, this study demonstrates that Cu_5.4O@CNDs exhibit significant potential for the treatment of various acute liver injury conditions, suggesting their promise as an intervention strategy for clinical application.