Direct Translocation as Major Cellular Uptake for CADY Self-Assembling Peptide-Based Nanoparticles 英文参考文献.docVIP

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Direct Translocation as Major Cellular Uptake for CADY Self-Assembling Peptide-Based Nanoparticles 英文参考文献.doc

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Direct Translocation as Major Cellular Uptake for CADY Self-Assembling Peptide-Based Nanoparticles 英文参考文献

DirectTranslocationasMajorCellularUptakeforCADY Self-AssemblingPeptide-BasedNanoparticles AnnaRydstro¨m1,Se′bastienDeshayes1,KaridiaKonate1,LaurenceCrombez1,Ka¨rtPadari2 ,Hassan Boukhaddaoui3,GudrunAldrian1,MargusPooga2,GillesDivita1* 1Centre de Recherches de Biochimie Macromole′culaire, CRBM-CNRS, UMR-5237, UM1-UM2, Department of Molecular Biophysics and Therapeutics, University of Montpellier,Montpellier,France,2DepartmentofDevelopmentalBiology,InstituteofMolecularandCellBiology,UniversityofTartu,Tartu,Estonia,3InstitutNationalde laSante′ etdelaRechercheMe′dicale(INSERM)U1051,InstitutdesNeurosciencesdeMontpellier,Montpellier,France Abstract CellpenetratingpeptidesconstituteapotentapproachtoovercomethelimitationsofinvivosiRNAdelivery.Werecently proposedapeptide-based nanoparticle system,CADY,forefficient deliveryofsiRNAintonumerouscelllines.CADYisa secondaryamphipathicpeptidethatformsstablecomplexeswithsiRNAtherebyimprovingboththeircellularuptakeand biological response. With the aim of understanding the cellular uptake mechanism of CADY:siRNA complexes, we have combinedbiochemical,confocalandelectronmicroscopyapproaches.Inthepresentwork,weprovideevidencethatthe majorrouteforCADY:siRNAcellularuptakeinvolvesdirecttranslocation throughthemembranebutnottheendosomal pathway.WehavedemonstratedthatCADY:siRNAcomplexesdonotcolocalizewithmostendosomalmarkersandremain fullyactiveinthepresenceofinhibitorsoftheendosomalpathway.Moreover,neitherelectrostatic interactionswithcell surface heparan sulphates nor membrane potential are essential for CADY:siRNA cell entry. In contrast, wehave shown thatCADY:siRNA complexes clearly induce atransient cellmembrane permeabilization, whichisrapidly restored bycell membrane fluidity. Therefore, we propose that direct translocation is the major gate for cell entry of CADY:siRNA complexes. Membraneperturbation anduptakearedrivenmainlybytheability ofCADYtointeract withphospholipids withinthecellmembrane,followedbyrapidlocaliza