Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers.
Journal
Nature communications
Journal Volume
15
Journal Issue
1
Start Page
Article number 3729
ISSN
2041-1723
Date Issued
2024-05-03
Author(s)
Wu, Man
Hau, Pok Man
Li, Linxian
Tsang, Chi Man
Yang, Yike
Taghbalout, Aziz
Chung, Grace Tin-Yun
Hui, Shin Yee
Tang, Wing Chung
Jillette, Nathaniel
Zhu, Jacqueline Jufen
Lee, Horace Hok Yeung
Kong, Ee Ling
Chan, Melissa Sue Ann
Chan, Jason Ying Kuen
Ma, Brigette Buig Yue
Lee, Charles
To, Ka Fai
Cheng, Albert Wu
Lo, Kwok-Wai
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.
SDGs
Type
journal article