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A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
Published on: May 10, 2022
HBV Envelope Protein-Bearing Vesicles Show Preferential Uptake in Hepatocyte-Derived Cells
Eri Takayama1, Misaki Enomoto1, Manami Nagae1
1Department of Cell Biology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan.
International Journal of Molecular Sciences
|May 27, 2026
Summary
This study introduces a novel virus-inspired vesicle platform for targeted delivery to liver cells. By displaying hepatitis B virus (HBV) proteins, these vesicles show enhanced uptake in hepatocytes, overcoming challenges in cell-type specificity for drug delivery.
Area of Science:
- Biotechnology
- Nanomedicine
- Virology
Background:
- Controlled drug delivery using nanoparticles faces challenges in achieving cell-type specificity.
- Hepatitis B virus (HBV) exhibits intrinsic tropism for hepatocytes, mediated by its large envelope (L) protein and host factors like sodium taurocholate cotransporting polypeptide (NTCP).
- Viral-like secretory vesicles (VLSVs) offer a potential platform for targeted delivery.
Purpose of the Study:
- To develop and evaluate a virus-inspired vesicle platform for targeted delivery to hepatocytes.
- To investigate the role of HBV L protein display on VLSVs for hepatocyte tropism.
- To optimize VLSV production and purification for enhanced protein content and targeting efficiency.
Main Methods:
- Improved production of VLSVs from HBV L- and S-expressing HEK293T cells using exosome-depleted fetal calf serum and optimized ultracentrifugation.
- Concentration of VLSVs using a sucrose cushion, labeling with DiI, and purification via sucrose density gradient ultracentrifugation.
- Evaluation of DiI-labeled VLSV uptake in various cell lines, including hepatocyte-derived (HepG2, Huh7) and non-hepatic cells, as well as NTCP-overexpressing HepG2 cells.
Main Results:
- Optimized VLSV production yielded approximately tenfold higher protein content per particle.
- VLSVs demonstrated preferential uptake in hepatocyte-derived cells, with the order: NTCP-overexpressing HepG2 > HepG2 > Huh7 > non-hepatic cells.
- Removal of the N-terminal Flag tag from the L protein enhanced hepatocyte-associated uptake, highlighting the importance of the native preS1 domain structure.
Conclusions:
- A virus-inspired vesicle platform displaying HBV spike proteins shows proof-of-concept for preferential uptake in hepatocyte-derived cells.
- The findings suggest that preserving the native structure of the HBV L protein's preS1 domain is crucial for enhanced hepatocyte targeting.
- This platform holds promise for advancing targeted delivery strategies in nanomedicine, particularly for liver-specific applications.
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