Hepatic stellate cells specific liposomes with the Toll-like receptor 4 shRNA attenuates liver fibrosis
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Updated: Nov 25, 2025
An Improved Time- and Labor- Efficient Protocol for Mouse Primary Hepatocyte Isolation
Published on: October 25, 2021
Yuwei Zhang1, Yang Li1, Tong Mu1
1Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
Abstract:
The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.
Insights
Vitamin A-coupled liposomes efficiently deliver TLR4 shRNA to hepatic stellate cells, inhibiting activation and reducing liver fibrosis. This targeted approach offers a promising therapeutic strategy for liver fibrosis.
Area of Science:
- Hepatology and Molecular Medicine
- Biotechnology and Drug Delivery
Background:
- Hepatic stellate cells (HSCs) are key drivers of liver fibrosis.
- Inhibiting HSC activation is a therapeutic target for liver fibrosis.
- RNA interference (RNAi) offers potential for TLR4 gene silencing in HSCs, but efficient delivery is challenging.
Purpose of the Study:
- To develop a targeted delivery system for RNAi targeting TLR4 in HSCs.
- To utilize vitamin A's affinity for HSCs to enhance delivery specificity.
- To evaluate the efficacy of vitamin A-coupled liposomes for TLR4 shRNA delivery and its impact on liver fibrosis.
Main Methods:
- Development of cationic liposomes modified with vitamin A (VitA-coupled liposomes).
- In vitro and in vivo assessment of VitA-coupled liposomes for delivering TLR4 shRNA to HSCs.
- Evaluation of TLR4 gene silencing effects on HSC activation, NF-κB pathway, pro-inflammatory cytokines, and reactive oxygen species (ROS).
Main Results:
- VitA-coupled liposomes demonstrated enhanced delivery of TLR4 shRNA to HSCs compared to uncoupled liposomes, both in vitro and in vivo.
- TLR4 gene silencing effectively inhibited HSC activation.
- The treatment attenuated liver fibrosis by inactivating the NF-κB pathway, reducing pro-inflammatory cytokine secretion, and decreasing ROS synthesis.
Conclusions:
- Vitamin A-coupled liposomes serve as an efficient and specific delivery vehicle for TLR4 shRNA in HSCs.
- Targeted TLR4 gene silencing via VitA-coupled liposomes presents a viable therapeutic strategy for mitigating liver fibrosis.
- This approach modulates key fibrotic pathways, including NF-κB signaling and oxidative stress.
