Liposome cocktail activator modulates hepatocytes and remodels the microenvironment to mitigate acute liver failure.

Acute liver failure (ALF) is a mortal and critical hepatic disease, in which oxidative stress, inflammation storm and hepatocyte death are crucial in the pathogenesis. Hence, in contrast to the control of a single link, a combination therapy targeting multiple pathogenic links of the disease will be a favorable means to control the progression of the disease. In this study, we constructed dimethyl itaconate-loaded liposomes modified with dodecyl gallate as a cocktail activator to investigate its functional role in acetaminophen (APAP)-induced ALF. Our results demonstrated that the cocktail activator acted on hepatocytes and triggered cocktail efficacy, thereby simultaneously attenuating APAP-induced hepatocyte damage and remodeling the damage microenvironment. The cocktail activator could effectively scavenge reactive oxygen species, inhibit excessive inflammatory responses and reduce cell death in impaired hepatocytes for detoxification. More importantly, the cocktail activator could remodel the damage microenvironment, thus further promoting hepatocyte expansion and specifically switching macrophages from the M1 to M2 phenotype for a favorable liver regeneration of ALF. Furthermore, in APAP-induced ALF mouse model, the cocktail activator improved liver function, alleviated histopathological damage and increased survival rate. In summary, these findings indicate that the cocktail activator may provide a promising therapeutic approach for ALF treatment as a nanomedicine.