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Peer-reviewedCC BY 4.0Exploration

A PD‐L1 Nanobody‐Engineered Synthetic RNA Virus Enhances Hepatocellular Carcinoma Immunotherapy by Interfering PCSK9 and Upregulating MHC‐I

  • Chuyu Huang1
  • Yun Ye1
  • Yi Guo2
  • Guozheng Liao2
  • Linyi Luo2
  • Lingwen Ding3
  • Yingling Miao1
  • Linping Zhao1
  • Yongchang Ouyang2
  • Shiying Li1
  1. 1Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, the School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou China
  2. 2GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University Guangzhou China
  3. 3Department of Pathology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore
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Abstract

Hepatocellular carcinoma (HCC) is characterized by low expression of major histocompatibility complex class I (MHC‐I), which significantly limits the efficacy of immunotherapy. In this work, bioinformatic analysis finds that elevated PCSK9 in HCC correlates with reduced T cell activity and poor prognosis. Based on these discoveries, a PD‐L1 nanobody‐engineered synthetic RNA virus (αPDL1‐VLPs/shPCSK9) is fabricated to inhibit PCSK9, thereby restoring MHC‐I expression to enhance HCC immunotherapy. The αPDL1‐VLPs/shPCSK9 is produced using MS2 virus‐like particles (VLPs) in Escherichia coli (E. coli), displaying PD‐L1 nanobodies and encapsulating PCSK9‐downregulating shRNA. Notably, αPDL1‐VLPs/shPCSK9 upregulates MHC‐I to enhance cytotoxic T lymphocytes (CTLs) recognition of tumor cells while promoting M2‐to‐M1 macrophages polarization, thereby boosting immunotherapy. In vivo studies indicate that αPDL1‐VLPs/shPCSK9 exhibits HCC tumor‐targeting behavior, suppressing primary tumor growth while avoiding systemic toxicity. Immunological analysis confirms that αPDL1‐VLPs/shPCSK9 enhances CTLs activation and infiltration, triggering systemic antitumor immunity to eradicate distant tumors. Overall, these findings highlight αPDL1‐VLPs/shPCSK9 as a promising therapeutic strategy for reversing the multiple immunosuppressive characteristics of HCC, providing a streamlined yet comprehensive approach to potentiate immunotherapy.

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Cite

BibTeXRIS
BibTeX
@article{huang2026pdl1,
  title = {{A PD‐L1 Nanobody‐Engineered Synthetic RNA Virus Enhances Hepatocellular Carcinoma Immunotherapy by Interfering PCSK9 and Upregulating MHC‐I}},
  author = {Chuyu Huang and Yun Ye and Yi Guo and Guozheng Liao and Linyi Luo and Lingwen Ding and Yingling Miao and Linping Zhao and Yongchang Ouyang and Shiying Li},
  journal = {Exploration},
  year = {2026},
  month = oct,
  doi = {10.1002/exp2.70226},
  url = {https://doi.org/10.1002/exp2.70226},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A PD‐L1 Nanobody‐Engineered Synthetic RNA Virus Enhances Hepatocellular Carcinoma Immunotherapy by Interfering PCSK9 and Upregulating MHC‐I
AU  - Chuyu Huang
AU  - Yun Ye
AU  - Yi Guo
AU  - Guozheng Liao
AU  - Linyi Luo
AU  - Lingwen Ding
AU  - Yingling Miao
AU  - Linping Zhao
AU  - Yongchang Ouyang
AU  - Shiying Li
PY  - 2026
DA  - 2026/10/06
JO  - Exploration
DO  - 10.1002/exp2.70226
UR  - https://doi.org/10.1002/exp2.70226
AB  - Hepatocellular carcinoma (HCC) is characterized by low expression of major histocompatibility complex class I (MHC‐I), which significantly limits the efficacy of immunotherapy. In this work, bioinformatic analysis finds that elevated PCSK9 in HCC correlates with reduced T cell activity and poor prognosis. Based on these discoveries, a PD‐L1 nanobody‐engineered synthetic RNA virus (αPDL1‐VLPs/shPCSK9) is fabricated to inhibit PCSK9, thereby restoring MHC‐I expression to enhance HCC immunotherapy. The αPDL1‐VLPs/shPCSK9 is produced using MS2 virus‐like particles (VLPs) in Escherichia coli (E. coli), displaying PD‐L1 nanobodies and encapsulating PCSK9‐downregulating shRNA. Notably, αPDL1‐VLPs/shPCSK9 upregulates MHC‐I to enhance cytotoxic T lymphocytes (CTLs) recognition of tumor cells while promoting M2‐to‐M1 macrophages polarization, thereby boosting immunotherapy. In vivo studies indicate that αPDL1‐VLPs/shPCSK9 exhibits HCC tumor‐targeting behavior, suppressing primary tumor growth while avoiding systemic toxicity. Immunological analysis confirms that αPDL1‐VLPs/shPCSK9 enhances CTLs activation and infiltration, triggering systemic antitumor immunity to eradicate distant tumors. Overall, these findings highlight αPDL1‐VLPs/shPCSK9 as a promising therapeutic strategy for reversing the multiple immunosuppressive characteristics of HCC, providing a streamlined yet comprehensive approach to potentiate immunotherapy.
SN  - 2766-8509
SN  - 2766-2098
ER  -