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Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated
Man Wu1,2, Pok Man Hau1, Linxian Li3,4,5
1Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
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.
Insights
Researchers developed a novel mRNA therapy (mTZ3-LNP) to reactivate Epstein-Barr virus (EBV) lytic cycle in EBV-positive cancers. This targeted approach shows potential for effective cancer treatment with enhanced safety.
Area of Science:
- Oncology
- Virology
- Nanomedicine
Background:
- Epstein-Barr virus (EBV) drives specific malignancies, making its latent-lytic switch a therapeutic target.
- Current treatments lack specific agents to induce the EBV lytic cycle in cancers, hindering clinical application.
Purpose of the Study:
- To develop a synthetic transcriptional activator for EBV lytic cycle induction.
- To evaluate the efficacy and safety of mRNA-nanoparticle delivery for EBV-targeted cancer therapy.
Main Methods:
- Synthesized a BZLF1-specific transcriptional activator encoded by mRNA.
- Encapsulated the mRNA in lipid nanoparticles (mTZ3-LNP) for targeted delivery.
- Assessed EBV lytic gene expression and tumor suppression in EBV-positive cancer models.
Main Results:
- mTZ3-LNP efficiently induced EBV lytic reactivation in EBV-positive cancer cells.
- Demonstrated potent and safe tumor growth suppression in preclinical models.
- Combination therapy with ganciclovir showed highly selective cytotoxicity against EBV-positive tumor cells.
Conclusions:
- mRNA-based nanomedicine offers a promising strategy for EBV-targeted cancer therapy.
- mTZ3-LNP effectively induces EBV lytic cycle and suppresses tumor growth.
- Combination therapy enhances selective killing of EBV-positive cancer cells.
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