Targeted delivery of anti-coxsackievirus siRNAs using ligand-conjugated packaging RNAs |
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Authors: | Huifang M. Zhang Yue Su Songchuan Guo Ji Yuan Travis Lim Jing Liu Peixuan Guo Decheng Yang |
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Affiliation: | aDepartment of Pathology and Laboratory Medicine, University of British Columbia, The Heart+Lung Institute, St. Paul's Hospital, Vancouver, Canada;bDepartment of Biomedical Engineering, College of Engineering/College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA |
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Abstract: | Coxsackievirus B3 (CVB3) is a common pathogen of myocarditis. We previously synthesized a siRNA targeting the CVB3 protease 2A (siRNA/2A) gene and achieved reduction of CVB3 replication by 92% in vitro. However, like other drugs under development, CVB3 siRNA faces a major challenge of targeted delivery. In this study, we investigated a novel approach to deliver CVB3 siRNAs to a specific cell population (e.g. HeLa cells containing folate receptor) using receptor ligand (folate)-linked packaging RNA (pRNA) from bacterial phage phi29. pRNA monomers can spontaneously form dimers and multimers under optimal conditions by base-pairing between their stem loops. By covalently linking a fluorescence-tag to folate, we delivered the conjugate specifically to HeLa cells without the need of transfection. We further demonstrated that pRNA covalently conjugated to siRNA/2A achieved an equivalent antiviral effect to that of the siRNA/2A alone. Finally, the drug targeted delivery was further evaluated by using pRNA monomers or dimers, which carried both the siRNA/2A and folate ligand and demonstrated that both of them strongly inhibited CVB3 replication. These data indicate that pRNA as a siRNA carrier can specifically deliver the drug to target cells via its ligand and specific receptor interaction and inhibit virus replication effectively. |
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Keywords: | Packaging RNA Coxsackievirus B3 Drug delivery Gene therapy Folate receptor siRNA |
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