miR-19b-3p engineered adipose-derived stem cell exosomes attenuate acute liver failure via promoting tissue repair and microenvironment remodeling.

Acute liver failure (ALF) is a life-threatening clinical syndrome, characterized by rapid hepatocyte injury and deteriorating hepatic microenvironment. To date, there is still no effective clinical treatment for ALF. Adipose-derived stem cells (ADSCs) have been proven to be an ideal seed-cell in tissue engineering and regenerative medicine through ADSCs-derived exosomes (ADSC-EXO) by paracrine effect. Herein, we presented an ADSC-EXO based therapeutic strategy that could facilitate microenvironment reconstruction and tissue repairing simultaneously in ALF. We demonstrated that miR-19b-3p exhibited remarkable anti-inflammation and anti-oxidation effect. Functionalized exosomes miR-19-EXO administration elevated survival rates from 25 % to 75 %, concurrently reversing liver function, promoting histoarchitectural integrity, and ameliorating inflammatory infiltration in vivo. Mechanistically, miR-19b-3p directly targeted p47phox (a NADPH oxidase subunit) and impede hepatic oxidative stress level. Then, the redox homeostasis changes inactivated NF-κB pathway by impeding iKBα ubiquitination and blocking nuclear translocation of NF-κB P65, and then triggered the damping of M1 macrophage polarization. Notably, miR-19-EXO also outperformed lentiviral miR-19b-3p or shp47phox delivery and conventional ROS scavengers in synergistic biological functions. Our finding paves the way of engineering ADSC-EXO to develop a proactive intervention strategy for ALF by increasing its specificity and functionality.