sEVsRVG selectively delivers antiviral siRNA to fetus brain, inhibits ZIKV infection and mitigates ZIKV-induced microcephaly in mouse model

  • Mol Ther. 2022 May 4;30(5):2078-2091. doi: 10.1016/j.ymthe.2021.10.009.
Rui Zhang  1 ,  Yuxuan Fu  2 ,  Min Cheng  1 ,  Wenyuan Ma  1 ,  Nan Zheng  1 ,  Yongxiang Wang  3 ,  Zhiwei Wu  4
Affiliations
  • 1. Center for Public Health Research, Medical School, Nanjing University, Nanjing, PR China.
  • 2. Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
  • 3. Department of Orthopedics, Northern Jiangsu People's Hospital, the Affiliated Hospital of Nanjing University Medical School, Yangzhou, China. Electronic address: [email protected].
  • 4. Center for Public Health Research, Medical School, Nanjing University, Nanjing, PR China; State Key Lab of Analytical Chemistry for Life Science, Nanjing University, Nanjing, PR China; Medical School and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, PR China. Electronic address: [email protected].
PMID: 34762817 DOI: 10.1016/j.ymthe.2021.10.009
Abstract

Zika virus (ZIKV), a Flavivirus associated with neurological disorders, constitutes a global health threat. During pregnancy, ZIKV traverses the placenta and causes congenital disease such as microcephaly and Guillain-Barré syndrome in newborns. To develop a specific Antiviral therapy against ZIKV-induced microcephaly that could cross placental and blood-brain barriers, we designed targeted small extracellular vesicles (sEVs) encapsulating Antiviral siRNA (small interfering RNA) to inhibit ZIKV. The neuro-specific targeting was achieved by engineering EVs membrane protein lamp2b fused with a neuron-specific rabies virus glycoprotein derived peptide (RVG). Intravenous administration of the RVG-engineered sEVs loaded with siRNA (ZIKV-specific siRNA) protected pregnant AG6 mice against vertical transmission of ZIKV. Particularly, sEVsRVG-siRNA traversed placental and blood-brain barriers and suppressed ZIKV Infection in fetal brains. Moreover, sEVsRVG-siRNA alleviated the neuroinflammation and neurological damage caused by ZIKV in the fetal mouse model. In general, we developed a sEVs-based targeted system of Antiviral therapy for brain and fetal brain infections.

Keywords
ZIKV; antiviral siRNA; microcephaly; rabies virus glycoprotein (RVG); sEVs; targeted delivery.
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