Vitamin A-coupled liposomes carrying TLR4-silencing shRNA induce apoptosis of pancreatic stellate cells and resolution of pancreatic fibrosis

Yuwei Zhang, Dan Yue, Liuliu Cheng, Anliang Huang, Nanwei Tong, Ping Cheng

Chronic pancreatitis leads to irreversible damage in pancreatic endocrine and exocrine functions. However, there is no clinically available antifibrotic drug. Pancreatic stellate cells (PSCs) can be activated by Toll-like receptor 4 (TLR4) responses to its ligands and they contribute to the formation of pancreatic fibrosis. Silencing the expression of TLR4 in PSCs by RNAi may be a novel therapeutic strategy for the treatment of pancreatic fibrosis. In addition, PSCs have a remarkable capacity for vitamin A uptake most likely through cellular retinol binding protein (CRBP). In our study, to ensure the efficient delivery of RNAi therapeutic agents to PSCs, VitA-coupled liposomes (VA-lips) were used as drug carriers to deliver plasmids expressing TLR4-specific short hairpin RNA (shRNA) to treat pancreatic fibrosis. Our study demonstrated that silencing the expression of TLR4 could induce mitochondrial apoptosis in aPSCs and might be an effective therapeutic strategy for the treatment of pancreatic fibrosis. VA-lip-shRNA-TLR4 recovers pancreatic tissue damage. VA-lip-shRNA-TLR4 resolution of pancreatic fibrosis. VA-lip-shRNA-TLR4 accelerates ECM degradation and inhibits ECM synthesis. Silencing TLR4 induces aPSCs mitochondrial apoptosis. Silencing TLR4 inhibits the activation of NF-κB.