Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease

Acta Biomater. 2024 Jan 15:174:281-296. doi: 10.1016/j.actbio.2023.10.038. Epub 2023 Nov 10.

Abstract

RNA interference (RNAi) presents great potential against intractable liver diseases. However, the establishment of specific, efficient, and safe delivery systems targeting hepatocytes remains a great challenge. Herein, we described a promising hepatocytes-targeting system through integrating triantennary N-acetylgalactosamine (GalNAc)-engineered cell membrane with biodegradable mesoporous silica nanoparticles, which efficiently and safely delivered siRNA to hepatocytes and silenced the target PCSK9 gene expression for the treatment of non-alcoholic fatty liver disease. Having optimized the GalNAc-engineering strategy, insertion orders, and cell membrane source, we obtained the best-performing GalNAc-formulations allowing strong hepatocyte-specific internalization with reduced Kupffer cell capture, resulting in robust gene silencing and less hepatotoxicity when compared with cationic lipid-based GalNAc-formulations. Consequently, a durable reduction of lipid accumulation and damage was achieved by systemic administering siRNAs targeting PCSK9 in high-fat diet-fed mice, accompanied by displaying desirable safety profiles. Taken together, this GalNAc-engineering biomimetics represented versatile, efficient, and safe carriers for the development of hepatocyte-specific gene therapeutics, and prevention of metabolic diseases. STATEMENT OF SIGNIFICANCE: Compared to MSN@LP-GN3 (MC3-LNP), MSN@CM-GN3 exhibited strong hepatocyte targeting and Kupffer cell escaping, as well as good biocompatibility for safe and efficient siRNA delivery. Furthermore, siPCSK9 delivered by MSN@CM-GN3 reduced both serum and liver LDL-C, TG, TC levels and lipid droplets in HFD-induced mice, resulting in better performance than MSN/siPCSK9@LP-GN3 in terms of lipid-lowering effect and safety profiles. These findings indicated promising advantages of our biomimetic GN3-based systems for hepatocyte-specific gene delivery in chronic liver diseases. Our work addressed the challenges associated with the lower targeting efficiency of cell membrane-mimetic drug delivery systems and the immunogenicity of traditional GalNAc delivery systems. In conclusion, this study provided an effective and versatile approach for efficient and safe gene editing using ligand-integrated biomimetic nanoplatforms.

Keywords: Biomimetic; Cell membrane; GalNAc; Hepatocyte-specific; PCSK9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomimetics
  • Hepatocytes / metabolism
  • Lipids / pharmacology
  • Liver / metabolism
  • Mice
  • Non-alcoholic Fatty Liver Disease* / genetics
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / therapy
  • Proprotein Convertase 9* / genetics
  • Proprotein Convertase 9* / metabolism
  • Proprotein Convertase 9* / pharmacology
  • RNA Interference
  • RNA, Small Interfering / pharmacology

Substances

  • PCSK9 protein, human
  • Proprotein Convertase 9
  • RNA, Small Interfering
  • Lipids