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Antiviral Res. 2018 Oct;158:147-160. doi: 10.1016/j.antiviral.2018.08.003. Epub 2018 Aug 6.

Inhibition of influenza A virus by mixed siRNAs, targeting the PA, NP, and NS genes, delivered by hybrid microcarriers.

Author information

1
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya, 29, 195251, St. Petersburg, Russian Federation. Electronic address: alexandra.b_05@mail.ru.
2
RASA Center, National Research Tomsk Polytechnic University, Lenin Avenue, 30, 634050, Tomsk, Russian Federation; First I. P. Pavlov State Medical University of St. Petersburg, Lev Tolstoy str., 6/8, 197022, St. Petersburg, Russian Federation. Electronic address: a_timin@mail.ru.
3
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; Institute of Cytology, Russian Academy of Sciences, Tikhoretsky ave. 4, 194064, St. Petersburg, Russian Federation.
4
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; First I. P. Pavlov State Medical University of St. Petersburg, Lev Tolstoy str., 6/8, 197022, St. Petersburg, Russian Federation.
5
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; St. Petersburg State University, Vasilyevsky Island, Liniya 16-ya, 29, 199178, St. Petersburg, Russian Federation.
6
Saratov State University, Astrakhanskaya Street 83, 410012, Saratov, Russian Federation.
7
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; Petersburg Nuclear Physics Institute in Honor of B. P. Konstantinov, National Research Center "Kurchatov Institute", 188300, Gatchina, Russian Federation.
8
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya, 29, 195251, St. Petersburg, Russian Federation.
9
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation.
10
Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya, 29, 195251, St. Petersburg, Russian Federation; School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, United Kingdom.
11
Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, Prof. Popova str., 15/17, 197376, St. Petersburg, Russian Federation; Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya, 29, 195251, St. Petersburg, Russian Federation; St. Petersburg State Chemical Pharmaceutical Academy, Prof. Popova str., 14 A, 197376, St. Petersburg, Russian Federation. Electronic address: vasin@influenza.spb.ru.

Abstract

In the present study, a highly effective carrier system has been developed for the delivery of antiviral siRNA mixtures. The developed hybrid microcarriers, made of biodegradable polymers and SiO2 nanostructures, more efficiently mediate cellular uptake of siRNA than commercially available liposome-based reagents and polyethyleneimine (PEI); they also demonstrate low in vitro toxicity and protection of siRNA from RNase degradation. A series of siRNA designs (targeting the most conserved regions of three influenza A virus (IAV) genes: NP, NS, and PA) were screened in vitro using RT-qPCR, ELISA analysis, and hemagglutination assay. Based on the results of screening, the three most effective siRNAs (PA-1630, NP-717, and NS-777) were selected for in situ encapsulation into hybrid microcarriers. It was revealed that pre-treatment of cells with a mixture of PA-1630, NP-717, and NS-777 siRNAs, delivered by hybrid microcarriers, provided stronger inhibition of viral M1 mRNA expression and control of NP protein level, after viral infection, than single pre-treatment by any of three encapsulated siRNAs used in the study. Moreover, the effective inhibition of replication in several IAV subtypes (H1N1, H1N1pdm, H5N2, and H7N9) using a cocktail of the three selected siRNAs, delivered by our hybrid capsules to the cells, was achieved. In conclusion, we have developed a proof-of-principle which shows that our hybrid microcarrier technology (utilizing a therapeutic siRNA cocktail) may represent a promising approach in anti-influenza therapy.

KEYWORDS:

Hybrid microcontainers; Influenza A virus; RNAi therapy; siRNA delivery

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