Deciphering the internalization mechanism of WRAP:siRNA nanoparticles

Biochimica Et Biophysica Acta. Biomembranes
Sebastien DeshayesPrisca Boisguerin

Abstract

Gene silencing mediated by double-stranded small interfering RNA (siRNA) has been widely investigated as a potential therapeutic approach for a variety of diseases and, indeed, the first therapeutic siRNA was approved by the FDA in 2018. As an alternative to the traditional delivery systems for nucleic acids, peptide-based nanoparticles (PBNs) have been applied successfully for siRNA delivery. Recently, we have developed amphipathic cell-penetrating peptides (CPPs), called WRAP allowing a rapid and efficient siRNA delivery into several cell lines at low doses (20 to 50 nM). In this study, using a highly specific gene silencing system, we aimed to elucidate the cellular uptake mechanism of WRAP:siRNA nanoparticles by combining biophysical, biological, confocal and electron microscopy approaches. We demonstrated that WRAP:siRNA complexes remain fully active in the presence of chemical inhibitors of different endosomal pathways suggesting a direct cell membrane translocation mechanism. Leakage studies on lipid vesicles indicated membrane destabilization properties of the nanoparticles and this was supported by the measurement of WRAP:siRNA internalization in dynamin triple-KO cells. However, we also observed some evidences for an ...Continue Reading

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Citations

Jun 3, 2021·Biomedicines·Prisca BoisguérinSébastien Deshayes
Aug 28, 2021·International Journal of Molecular Sciences·Shabnam TarvirdipourCornelia G Palivan
Nov 4, 2021·Cell Reports·Evgeniya TrofimenkoChristian Widmann

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