Multifunctional integrated polyphenol-copper nanozymes for sepsis-induced acute liver injury via ameliorating endoplasmic reticulum stress and reprogramming inflammatory microenvironment

Abstract

Acute liver injury is a common complication of sepsis, making it one of the most challenging problems in intensive clinical care. Currently, no specific therapies are available for sepsis and sepsis-induced liver injury. Herein, we developed novel multifunctional polyphenol-copper nanozymes (Cu-CA NZs) with excellent biocompatibility and explored their therapeutic effect in sepsis and sepsis-induced acute liver injury. The Cu-CA NZs exhibited broad-spectrum non-antibiotic antibacterial and robust cascade superoxide dismutase- and catalase-mimicking activities. Further, the Cu-CA NZs diminished the lipopolysaccharide-induced inflammatory response and decreased mitochondrial damage in an in vitro macrophage inflammatory model. Moreover, Cu-CA NZs treatment dramatically mitigated liver injury biomarkers in the plasma, reduced hepatic oxidative stress and inflammatory responses, stimulated hepatic M1-type to M2 macrophage polarization, and improved the survival rate of septic mice. Mechanistically, the therapeutic effect of Cu-CA NZs may be mediated by alleviating excessive endoplasmic reticulum stress in the liver via the eIF2α/ATF4/CHOP pathway during sepsis. Thus, Cu-CA NZs are promising therapeutic candidates for treating sepsis and other inflammatory diseases.