EVs Containing Host Restriction Factor IFITM3 Inhibited ZIKV Infection of Fetuses in Pregnant Mice through Trans-placenta Delivery

Zika virus (ZIKV) infection can lead to neurological complications and fetal defects, and it has attracted global public health concerns. Effective treatment for ZIKV infection remains elusive, and a preventative vaccine is not yet available. Therapeutics for fetuses need to overcome placenta barriers to reach the fetuses and require higher safety standards. In the present study, we engineered mammalian extracellular vesicles (EVs) to deliver a host restriction factor, interferon-induced transmembrane protein 3 (IFITM3), for the treatment of ZIKV infection. Our results demonstrated that the IFITM3-containing EVs (IFITM3-Exos) suppressed ZIKV viremia by a 2-log reduction in pregnant mice. Moreover, the engineered EVs effectively delivered IFITM3 protein across the placental barrier and suppressed ZIKV in the fetuses with significant reduction of viremia in key fetal organs as measured by quantitative real-time PCR. Mechanistic study showed that IFITM3 was delivered to late endosomes/lysosomes where it inhibited viral entry into the host cells. Our study demonstrated that EVs could act as a cross-placenta drug delivery vehicle to the fetus, and IFITM3, an endogenous restriction factor, is a potential treatment for ZIKV infection during pregnancy.