Internalization

Gene

microRNA

Cell biology

Biology

Microvesicles

Cancer research

Biochemistry

Small interfering RNA

Transfection

Gene silencing

Endocytosis

Genetics

Endosome

Folate receptor

RNA interference

Exosome

Gene knockdown

Chemistry

Cell

Cancer

Cancer cell

Journal of Controlled Release

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 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, 14,644). 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.

Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping