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

Autor: Wu M; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.; State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China., Hau PM; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Li L; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Shatin, Hong Kong SAR, China.; Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.; Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Hong Kong SAR, China., Tsang CM; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.; State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China., Yang Y; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Shatin, Hong Kong SAR, China.; College of Chemistry and Green Catalysis Center, Zhengzhou University, Zhengzhou, China., Taghbalout A; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA., Chung GT; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Hui SY; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Tang WC; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Jillette N; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA., Zhu JJ; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.; School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA., Lee HHY; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Shatin, Hong Kong SAR, China., Kong EL; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Chan MSA; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Chan JYK; Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China., Ma BBY; Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Charlie Lee Precision Immuno-oncology program, Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China., Chen MR; Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, 100233, Taiwan., Lee C; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA., To KF; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.; State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China., Cheng AW; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA. albert.cheng@ioz.ac.cn.; School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85281, USA. albert.cheng@ioz.ac.cn.; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, 06030, USA. albert.cheng@ioz.ac.cn.; Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT, 06030, USA. albert.cheng@ioz.ac.cn.; The Jackson Laboratory Cancer Center, Bar Harbor, ME, 04609, USA. albert.cheng@ioz.ac.cn.; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. albert.cheng@ioz.ac.cn.; Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of Sciences, Beijing, China. albert.cheng@ioz.ac.cn.; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. albert.cheng@ioz.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. albert.cheng@ioz.ac.cn., Lo KW; Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China. kwlo@cuhk.edu.hk.; State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China. kwlo@cuhk.edu.hk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 03; Vol. 15 (1), pp. 3729. Date of Electronic Publication: 2024 May 03.
DOI: 10.1038/s41467-024-48031-8
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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