Asialoglycoprotein receptor-bound PLGA nanoparticles loaded with Riociguat targetedly ameliorate portal hypertension...

Portal hypertension typically arises with liver cirrhosis and often leads to life-threatening side effects that complicate treatment. Although administrations of vasodilation drugs and/or transjugular intrahepatic portosystemic shunt have been widely used to treat portal hypertension in the clinic, they are usually less satisfactory because those methods may dramatically influence the entire cardiovascular system rather than the liver alone, indicating that an effective and safe approach for reducing cirrhotic portal hypertension is still strongly demanded nowadays. To meet the requirements, asialoglycoprotein receptor (ASGPR)-bound Riociguat-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles, named ARPNPs, were developed in this study. The ARPNPs were formed in spherical morphology with size of 254.78 ± 13.53 nm and zeta potential of -17.54 ± 1.89 mV. The surface modification with anti-ASGPR monoclonal antibodies enabled hepatocyte-binding specificity for ARPNPs. In comparison to the cirrhotic rats treated with free Riociguat, those treated with ARPNPs showed a significant increase in mean arterial pressure and superior mesenteric artery flow, while the hepatic vascular resistance, but not systemic vascular resistance, was noticeably reduced. Through the histological and RNA-seq analyses, we further demonstrated that the ARPNPs can upregulate eNOS and cGMP expressions in liver without systemic toxicity, showing that delivery of Riociguat via ARPNPs can certainly ameliorate portal hypertension and minimize systemic side effects in vivo. Considering the above effectiveness together with the advantages of biocompatibility and drug-release controllability of the PLGA nanocarriers, we anticipate that the developed ARPNPs are highly potential for use in the reduction of portal hypertension caused by liver cirrhosis.