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Abstract
Folate (FA) receptor is a cell surface glycoprotein overexpressed on many cancer cells.
It is a high affinity ligand for cancer cell targeting. However, delivery of siRNA
directly through folate receptor mediated endocytosis for gene silencing has not,
if any, been successful in cell culture, animal models or clinical trial. We have
reported the application of RNA nanotechnology to construct FA-displaying exosomes
for efficient cell targeting, siRNA delivery and cancer regression (Pi et.al Nature
Nanotechnology, 2018:13, 82–89; Li et.al., Scientific Report, 2018:8, 14644). However,
the mechanism underlying the efficient therapeutic behavior through folate/exosome
complex remains elusive. Here we demonstrate that the efficient cancer suppression
with the FA-displaying exosome was due to the receptor-mediated cytosol delivery of
the siRNA payload without endosome trapping, as attested by fluorescence colocalization
analysis, gene knockdown assay and animal tumor regression. It is expected that the
high potency of FA-displaying exosome in cytosolic siRNA delivery will renew the concept
and interest in using FA as cancer targeting ligand in human cancer therapy.