Hepatocyte-targeted hyaluronic acid-polyethyleneimine conjugates for acute liver injury therapy by ROS elimination and inflammation modulation

[Display omitted] •HA-PEI actively targets the liver through the CD44 receptor to reduce the off-target effects of PEI (highest effect at 1000 K).•This study provided a therapeutic agent for late-stage liver injury induced by acetaminophen that outperforms the FDA-approved drug N-acetylcysteine.•HA-PEI could increase oxygen content, eliminate ROS, and maintain mitochondrial membrane potential to protect hepatocytes that are under oxidative stress and inhibit the secretion of inflammatory factors to block the migration of immune cells to the liver, safeguarding hepatocytes from secondary damage. Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect.