Therapeutic Lipid Nanoparticles Delivery of Small Interfering RNA for the Synergistic Treatment of Hepatic Inflammation

Abstract Small interfering RNA (siRNA) against tumor necrosis factor‐alpha (TNF‐α) is a valuable therapeutic agent for hepatic inflammation. However, lipid nanoparticles (LNPs), the most clinically advanced vectors for delivering siRNA to the liver, have no therapeutic effect on diseases themselves. Here, therapeutic L‐LNPs are developed by replacing the helper lipid in Onpattro with 1,2‐dilauryl‐sn‐glycero‐3‐phosphocholine (DLPC). Cy5‐siRNA in screened L2‐3@siRNA has comparable liver accumulation with that of initial LNPs without DLPC. L2‐3@siTNF‐α can significantly block TNF‐α production in vitro and in vivo. The findings demonstrate that DLPC in L2‐3@siRNA can decrease the phosphorylation of extracellular signal‐regulated kinase 1/2 in the MARK signaling pathway and reduce the production of TNF‐α. Meanwhile, the loaded siTNF‐α can effectively silence the expression of the TNF‐α gene through RNA interference. The synergistic therapeutic effect of L2‐3@siTNF‐α results in an excellent anti‐inflammatory effect in treating hepatic inflammation with good biocompatibility. Therefore, this work would provide a promising platform for the safe and effective treatment of hepatic inflammation.