Affiliation:
1. Second Affiliated Hospital, Zhejiang University School of Medicine,
2. Qilu Hospital of Shandong University
3. Zhejiang University School of Medicine
4. The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases
5. Zhejiang Cancer Hospital
6. Shandong University
Abstract
Abstract
Liver diseases, including acute liver failure (ALF), non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), are associated with high morbidity and mortality. However, the therapeutic options for liver diseases are currently limited. In this study, we have shown for the first time that red blood cell-derived extracellular vesicles (RBC-EVs) modified with triantennary N-acetyl galactosamine-(GalNac) sequences (GalNac-RBC-EVs) can selectively target hepatocytes as opposed to Kupffer cells via the asialoglycoprotein receptors (ASGPR) expressed on the former. Furthermore, RBC-EVs loaded with GalNac-miR-155-ASO (RBC-EVs/GalNac-miR-155-ASO) significantly reduced the mortality of mice with ALF, and alleviated pyroptosis, apoptosis and necroptosis (PANoptosis) of the hepatocytes. Likewise, PJ34-loaded GalNac-RBC-EVs (GalNac-RBC-EVs/PJ34) significantly improved the symptoms of NAFLD and stalled HCC progression in mouse models by inhibiting PARP-1. Furthermore, incorporation of Rab7-siRNA reduced PJ34 degradation in hepatocytes, thereby enhancing the therapeutic efficacy of GalNac-RBC-EVs/PJ34. Finally, the GalNac-RBC-EVs were well-tolerated and did not induce any systemic toxicity, or damage to vital organs. In conclusion, GalNac-modified RBC-EVs are a promising drug carrier for the precise treatment of various liver diseases based on their ability to specifically target hepatocytes.
Publisher
Research Square Platform LLC