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

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 Lee, Ee Ling Kong, Melissa Sue Ann Chan, Jason Ying Kuen Chan, Brigette Buig Yue Ma, Mei-Ru Chen, Charles Lee, Ka Fai To, Albert Wu Cheng () and Kwok-Wai Lo ()
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Man Wu: 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
Chi Man Tsang: The Chinese University of Hong Kong
Yike Yang: Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet
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
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
Albert Wu Cheng: The Jackson Laboratory for Genomic Medicine
Kwok-Wai Lo: The Chinese University of Hong Kong

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48031-8

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