Abstract
Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.
Highlights
Viral-based delivery systems for nucleic acids have demonstrated high levels of transfection efficiency and highly potent delivery[1], but are hampered by their known side effects such as immunogenicity and have not made it into clinical practice[2]
We evaluated the therapeutic potential of targeting hepatocytes in hepatocellular carcinoma (HCC), using lipid nanoparticles (LNPs)-based delivery of small interfering RNA directed against Jnk[2]
In order to explore a new concept for the treatment of liver cancer, we comprehensively studied the functions of Jnk[2] in a genetically determined HCC mouse model, the NEMOΔHepa mouse
Summary
Viral-based delivery systems for nucleic acids have demonstrated high levels of transfection efficiency and highly potent delivery[1], but are hampered by their known side effects such as immunogenicity and have not made it into clinical practice[2]. While RNA delivery has been an obstacle for decades, lipid-based delivery. Significant progress has been made to overcome some of the obstacles associated with in vivo delivery of siRNA, and lipid nanoparticles (LNPs) are very promising tools. LNPs are known to interact with serum proteins, exchanging components and acquiring proteins in circulation that can potentially direct LNPs to specific cell types[6]. It is well-known that siRNA-loaded LNP absorb Apolipoprotein E (ApoE) on their surface, enhancing uptake into hepatoma cells and primary hepatocytes[6,7]. LNPs behave as neutral liposomes in circulation, acquiring ApoE and delivering siRNA to hepatocytes in a targeted manner
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