Inhibiting hepatic gluconeogenesis by chitosan lactate nanoparticles containing CRTC2 siRNA targeted by poly(ethylene glycol)-glycyrrhetinic acid.

Diabetes mellitus is a chronic metabolic disorder characterized by insulin deficiency and impaired glucose metabolism. Overexpression of cAMP response element binding protein (CREB)-regulated transcriptional coactivator 2 (CRTC2) plays an important role in high gluconeogenesis in patients with diabetes type II. Using RNA interference technology for silencing CRTC2 gene expression could be helpful in controlling the level of blood glucose and gluconeogenesis. In this study, we designed a siRNA delivery platform comprising blended chitosan lactate (CT) and polyethylene glycol (PEG) conjugated with glycyrrhetinic acid (GA) for controlling gluconeogenesis. The nanoparticles showed spherical and smooth surface with ~ 189-nm size and + 5.1 zeta potential. Targeted nanoparticles were efficiently stable in serum and different levels of heparin media over 48 h. The gene knockdown efficiency of nanoparticles was comparable to Lipofectamine®, while they had no significant in vitro and in vivo toxicity. The in vivo therapeutic efficacy of targeted nanoparticles was also confirmed by reduced amount of fasting blood sugar in diabetic rat models. Furthermore, the nanoparticles were mostly accumulated in the liver after 2 h indicating the significant targeting ability of the prepared nanoparticles. Therefore, CT/PEG-GA nanoparticles can be considered as a potential candidate for targeted delivery of siRNA into hepatocytes in order to regulate gluconeogenesis in diabetes.