Article
Author: Ma, Brigette Buig Yue ; Taghbalout, Aziz ; Chan, Jason Ying Kuen ; Lee, Charles ; Chan, Melissa Sue Ann ; Kong, Ee Ling ; Hui, Shin Yee ; Chen, Mei-Ru ; Tsang, Chi Man ; Jillette, Nathaniel ; Zhu, Jacqueline Jufen ; Lee, Horace Hok Yeung ; Lo, Kwok-Wai ; Tang, Wing Chung ; Chung, Grace Tin-Yun ; Li, Linxian ; Wu, Man ; Yang, Yike ; Cheng, Albert Wu ; Hau, Pok Man ; To, Ka Fai
AbstractThe 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.