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Ultrasound-Responsive Dual-Prodrug Nanoassembly for "Fenestrae-Restoration Strategy" in Liver Fibrosis Therapy
Shutong Liu1, Mengyao Zhang1, Zitong Qiu1
1Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, P. R. China.
Abstract:
Liver fibrosis is a serious yet reversible intermediate stage in the progression of liver disease, which can ultimately advance to cirrhosis and hepatocellular carcinoma. Targeted and selective inhibition of activated hepatic stellate cells (aHSCs) has emerged as a promising therapeutic strategy for the treatment of liver fibrosis. However, the capillarization of liver sinusoidal endothelial cells (LSECs) characterized by the loss of fenestrae and continuous formation of basement membrane presents a significant barrier to effective delivery of anti-fibrotic agents. In this study, we propose a novel "fenestrae-restoration strategy" employing ultrasound-responsive polymeric dual prodrug nanoassembly (PMS) co-loaded with nitric oxide prodrug (mSNO) and poly-metformin (PMet). PMS is engineered for controllable, ultrasound-triggered release of nitric oxide from mSNO, which activates soluble guanylate cyclase. This results in upregulation of intracellular cyclic guanosine monophosphate that facilitates the reversal of LSECs capillarization, restoring fenestrae and enhancing endothelial permeability. This restoration enables PMS to traverse the hepatic sinusoidal barrier, followed by accumulation in fibrotic tissue, where PMet is internalized by aHSCs. In lysosomes, metformin released from PMet ultimately inhibits aHSCs proliferation and migration via the AMPK-mTOR pathway deregulation. The therapeutic efficacy and underlying mechanisms of "fenestrae-restoring strategy" were comprehensively validated in preclinical CCl4-induced murine model of liver fibrosis. These findings provide interesting insights into the combination therapy of liver fibrosis and paves new avenues for future development of smart therapeutic modalities utilizing stimuli-responsive biosafe nanotherapeutics.
Insights
This study introduces a novel nanotherapy that restores liver sinusoidal endothelial cell fenestrae, enabling drug delivery to inhibit activated hepatic stellate cells and treat liver fibrosis.
Area of Science:
- Hepatology and Nanomedicine
- Drug Delivery Systems
- Fibrosis Research
Background:
- Liver fibrosis is a precursor to cirrhosis and cancer, with activated hepatic stellate cells (aHSCs) as key drivers.
- Capillarization of liver sinusoidal endothelial cells (LSECs) impedes anti-fibrotic drug delivery.
- Targeting aHSCs is a promising strategy, but delivery barriers must be overcome.
Purpose of the Study:
- To develop a novel nanotherapeutic strategy for liver fibrosis treatment.
- To overcome the LSEC barrier using a fenestrae-restoration approach.
- To co-deliver nitric oxide and metformin to target both LSECs and aHSCs.
Main Methods:
- Ultrasound-responsive polymeric dual prodrug nanoassembly (PMS) co-loaded with nitric oxide prodrug (mSNO) and poly-metformin (PMet).
- Ultrasound-triggered release of nitric oxide to restore LSEC fenestrae and permeability.
- Internalization of PMet by aHSCs for metformin release and inhibition of proliferation/migration via AMPK-mTOR pathway.
Main Results:
- The fenestrae-restoration strategy successfully enhanced nanoparticle traversal across the hepatic sinusoidal barrier.
- Nitric oxide release reversed LSEC capillarization, restoring fenestrae.
- Metformin effectively inhibited aHSCs proliferation and migration in a preclinical liver fibrosis model.
Conclusions:
- The developed nanotherapy shows significant potential for treating liver fibrosis by addressing delivery barriers and targeting key cellular mechanisms.
- This stimuli-responsive nanotherapeutic approach offers a promising combination therapy for liver fibrosis.
- Further development of such smart nanotherapeutics could revolutionize liver disease treatment.
