Tomeetthecriteriaforefficientdelivery,thecationicamphiphilesystemcondensesthereporter-DNAbydisplacementofthepositivelycharged(inorganic)counterionsand,afterbinding,'transports'theso-formedlipoplextothecellsurface.Duringthesestages,DNAprotectionandpreservationofthelipoplexmorphologyareimportantissues.Afterreachingthecellsurface,interactionofthepositivelychargedlipoplexwiththenegativelychargedplasmamembraneofthecellisfacilitated,initiatingthemembranetransferprocesses.ThesubsequentpassageacrossthecellmembraneandescapeoftheDNAmaterailintothecytoplasmfinalizethefirstpartofthistrajectory.Endocytosispositivelyinfluencesthispartofthesequence,whichinvolvesthereleaseofDNAfromtheendosomalcompartment,facilitatedbyanasyetlargelyunresolvedmechanismofdisruptionoftheendosomalmembrane.stagesinthepathwayclearlybenefitfromradicallydifferenttypesofmorphologicalbehaviorofthelipoplexandtheconstitutinglipids.

Apotentialmethodofimprovingthedeliverycapabilitiesofsyntheticbilayer-formingamphiphilesistoinduceamorphologicalchangeofthelipoplexfromarelativestablelamellarphase(DNAcondensingmorphology)intoaninvertedhexagonalphase(H11),recognizedasthemosteffectivemorphologyforinvitrotransfection.Thehexagonalphasemorphologydoesnotnecessarilyfacilitatetheinteractionwiththecellmembranebutappearspivotalfortheescapefromtheendosomalcompartment.Preferably,themorphologicalchangesareonlyinducedintheproximityoforaftercontactwiththecellmembraneor,alternatively,attheendosomallevel.Thisrationalhasbeenappliedtothedesignofnovelcytofectins,theso-calledSunfishamphiphiles(Scheme1),byattachingaflexible"antenna"tothecationicheadgroupratherthanamethylmoiety,asinthestructurallyrelatedSAINTamphiphiles2.

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