Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers.
Humans
Herpesvirus 4, Human
/ genetics
Trans-Activators
/ metabolism
Epstein-Barr Virus Infections
/ virology
Animals
Nanoparticles
/ chemistry
Cell Line, Tumor
Mice
RNA, Messenger
/ genetics
Virus Activation
/ drug effects
Xenograft Model Antitumor Assays
Gene Expression Regulation, Viral
/ drug effects
Mice, Nude
Female
Liposomes
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 May 2024
03 May 2024
Historique:
received:
07
06
2023
accepted:
17
04
2024
medline:
4
5
2024
pubmed:
4
5
2024
entrez:
3
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38702330
doi: 10.1038/s41467-024-48031-8
pii: 10.1038/s41467-024-48031-8
doi:
Substances chimiques
BZLF1 protein, Herpesvirus 4, Human
0
Trans-Activators
0
Lipid Nanoparticles
0
RNA, Messenger
0
Liposomes
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3729Informations de copyright
© 2024. The Author(s).
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