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

作者：He, Xuan; Chang, Zhimin; Chen, Fangman^*; Zhang, Wensheng; Sun, Madi; Shi, Tongfei; Liu, Jie; Chen, Peiyu; Zhang, Kunbao; Guan, Shan; Zhao, Zhibin; Li, Mingqiang; Dong, Wen-fei; Shao, Dan^*; Yang, Chao^*

来源：Acta Biomaterialia, 2024, 174: 281-296.

DOI：10.1016/j.actbio.2023.10.038

• Biomimetic
• Hepatocyte-specific
• Cell membrane
• GalNAc
• PCSK9

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 trianten-nary 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.

• 单位
  南方医科大学; 中山大学; 中国科学院