Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment

Abstract

Liver cirrhosis is a liver disease with a high mortality rate worldwide, and antifibrotic drugs are commonly used clinically to alleviate the symptoms, but there are still many challenges. Many studies have shown that excessive reactive oxygen species (ROS) in the microenvironment of liver lesions is an important factor leading to the development of liver cirrhosis. Herein, a nanomedicine-mediated antioxidant therapy was utilized to remodel liver microenvironment and hence reverse the process of cirrhosis from the root. Firstly, L-arginine (L-Arg) loaded and pPB peptide modified PEGylated hollow polydopamine (HPDA) nanoparticles (L-Arg@HPDA-PEG-pPB, L@HPp) were prepared successfully. The in vitro and in vivo experiment showed that L@HPp significantly inhibited oxidative stress and inflammatory reaction, reduced the activation of hepatic stellate cells (HSCs), inhibited the pro-fibrosis molecular pathway, and reduced the deposition of extracellular matrix (ECM), thereby effectively inhibiting liver fibrosis. The pPB peptide modification increased the targeting effect to HSCs. In addition, the oxidative microenvironment in liver cirrhosis promoted the transformation of the loaded L-Arg to nitric oxide (NO), and the latter one caused vascular dilation and further relieved portal hypertension, a typical complication of liver cirrhosis. Therefore, L@HPp had a good prospect of clinical application in the treatment of liver cirrhosis and its complications.