Document Type
Article
Publication Date
5-3-2024
Original Citation
Wu M,
Hau P,
Li L,
Tsang C,
Yang Y,
Taghbalout A,
Chung G,
Hui S,
Tang W,
Jillette NL,
Zhu J,
Lee H,
Kong E,
Chan M,
Chan J,
Ma B,
Chen M,
Lee C,
To K,
Cheng A,
Lo K.
Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers. Nat Commun. 2024;15(1):3729
Keywords
JGM, JMG, Humans, Herpesvirus 4, Human, Trans-Activators, Epstein-Barr Virus Infections, Animals, Nanoparticles, Cell Line, Tumor, Mice, RNA, Messenger, Virus Activation, Xenograft Model Antitumor Assays, Gene Expression Regulation, Viral, Mice, Nude, Female, Liposomes
JAX Source
Nat Commun. 2024;15(1):3729
ISSN
2041-1723
PMID
38702330
DOI
https://doi.org/10.1038/s41467-024-48031-8
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.