Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12

Mol Ther. 2021 Aug 4;29(8):2424-2440. doi: 10.1016/j.ymthe.2021.05.005. Epub 2021 May 11.


Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.

Keywords: ACE2; IL-1β; IL-6; NF-κB; Nsp12; SARS-CoV-2; TNF-α; exosomes; ginger exosome-like nanoparticle; lung epithelial cells; lung inflammation; macrophages; microRNA; spike.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • COVID-19 / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cytokines / metabolism
  • Epithelial Cells / metabolism
  • Exosomes / metabolism*
  • Humans
  • Interleukin-6 / metabolism
  • Macrophages, Alveolar / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • NF-kappa B / metabolism
  • Plants / metabolism*
  • Pneumonia / metabolism*
  • SARS-CoV-2 / pathogenicity
  • Tumor Necrosis Factor-alpha / metabolism
  • U937 Cells
  • Vero Cells


  • Cytokines
  • Interleukin-6
  • MicroRNAs
  • NF-kappa B
  • Tumor Necrosis Factor-alpha