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Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers

Author

Listed:
  • Man Wu

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Pok Man Hau

    (The Chinese University of Hong Kong)

  • Linxian Li

    (Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet
    The Chinese University of Hong Kong
    Hong Kong Science Park)

  • Chi Man Tsang

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Yike Yang

    (Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet
    Zhengzhou University)

  • Aziz Taghbalout

    (The Jackson Laboratory for Genomic Medicine)

  • Grace Tin-Yun Chung

    (The Chinese University of Hong Kong)

  • Shin Yee Hui

    (The Chinese University of Hong Kong)

  • Wing Chung Tang

    (The Chinese University of Hong Kong)

  • Nathaniel Jillette

    (The Jackson Laboratory for Genomic Medicine)

  • Jacqueline Jufen Zhu

    (The Jackson Laboratory for Genomic Medicine
    Arizona State University)

  • Horace Hok Yeung Lee

    (Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet)

  • Ee Ling Kong

    (The Chinese University of Hong Kong)

  • Melissa Sue Ann Chan

    (The Chinese University of Hong Kong)

  • Jason Ying Kuen Chan

    (The Chinese University of Hong Kong)

  • Brigette Buig Yue Ma

    (The Chinese University of Hong Kong)

  • Mei-Ru Chen

    (National Taiwan University)

  • Charles Lee

    (The Jackson Laboratory for Genomic Medicine)

  • Ka Fai To

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Albert Wu Cheng

    (The Jackson Laboratory for Genomic Medicine
    Arizona State University
    University of Connecticut Health Center
    University of Connecticut Health Center)

  • Kwok-Wai Lo

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

Abstract

The unique virus-cell interaction in Epstein-Barr virus (EBV)-associated malignancies implies targeting the viral latent-lytic switch is a promising therapeutic strategy. However, the lack of specific and efficient therapeutic agents to induce lytic cycle in these cancers is a major challenge facing clinical implementation. We develop a synthetic transcriptional activator that specifically activates endogenous BZLF1 and efficiently induces lytic reactivation in EBV-positive cancer cells. A lipid nanoparticle encapsulating nucleoside-modified mRNA which encodes a BZLF1-specific transcriptional activator (mTZ3-LNP) is synthesized for EBV-targeted therapy. Compared with conventional chemical inducers, mTZ3-LNP more efficiently activates EBV lytic gene expression in EBV-associated epithelial cancers. Here we show the potency and safety of treatment with mTZ3-LNP to suppress tumor growth in EBV-positive cancer models. The combination of mTZ3-LNP and ganciclovir yields highly selective cytotoxic effects of mRNA-based lytic induction therapy against EBV-positive tumor cells, indicating the potential of mRNA nanomedicine in the treatment of EBV-associated epithelial cancers.

Suggested Citation

  • Man Wu & Pok Man Hau & Linxian Li & Chi Man Tsang & Yike Yang & Aziz Taghbalout & Grace Tin-Yun Chung & Shin Yee Hui & Wing Chung Tang & Nathaniel Jillette & Jacqueline Jufen Zhu & Horace Hok Yeung Le, 2024. "Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48031-8
    DOI: 10.1038/s41467-024-48031-8
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    References listed on IDEAS

    as
    1. Lei Miao & Jiaqi Lin & Yuxuan Huang & Linxian Li & Derfogail Delcassian & Yifan Ge & Yunhua Shi & Daniel G. Anderson, 2020. "Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Weitao Lin & Yim Ling Yip & Lin Jia & Wen Deng & Hong Zheng & Wei Dai & Josephine Mun Yee Ko & Kwok Wai Lo & Grace Tin Yun Chung & Kevin Y. Yip & Sau-Dan Lee & Johnny Sheung-Him Kwan & Jun Zhang & Ten, 2018. "Establishment and characterization of new tumor xenografts and cancer cell lines from EBV-positive nasopharyngeal carcinoma," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    3. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Author Correction: Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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