IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48031-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48031-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-48031-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Kai Liu & Ralf Nilsson & Elisa Lázaro-Ibáñez & Hanna Duàn & Tasso Miliotis & Marie Strimfors & Michael Lerche & Ana Rita Salgado Ribeiro & Johan Ulander & Daniel Lindén & Anna Salvati & Alan Sabirsh, 2023. "Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Roy Pattipeiluhu & Ye Zeng & Marco M.R.M. Hendrix & Ilja K. Voets & Alexander Kros & Thomas H. Sharp, 2024. "Liquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Xuexiang Han & Junchao Xu & Ying Xu & Mohamad-Gabriel Alameh & Lulu Xue & Ningqiang Gong & Rakan El-Mayta & Rohan Palanki & Claude C. Warzecha & Gan Zhao & Andrew E. Vaughan & James M. Wilson & Drew W, 2024. "In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Xuexiang Han & Hanwen Zhang & Kamila Butowska & Kelsey L. Swingle & Mohamad-Gabriel Alameh & Drew Weissman & Michael J. Mitchell, 2021. "An ionizable lipid toolbox for RNA delivery," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
    5. Lanqi Gong & Jie Luo & Yu Zhang & Yuma Yang & Shanshan Li & Xiaona Fang & Baifeng Zhang & Jiao Huang & Larry Ka-Yue Chow & Dittman Chung & Jinlin Huang & Cuicui Huang & Qin Liu & Lu Bai & Yuen Chak Ti, 2023. "Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48031-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.