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Tuning the Topological Landscape of DNA–Cyclodextrin Nanocomplexes by Molecular Design
Author(s) -
Neva Tania,
CarbajoGordillo Ana I.,
Benito Juan M.,
Lana Hugo,
Marcelo Gema,
Ortiz Mellet Carmen,
Tros de Ilarduya Conchita,
Mendicuti Francisco,
García Fernández José M.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002951
Subject(s) - transfection , supramolecular chemistry , biophysics , dna , cyclodextrin , dna origami , gene delivery , dispersity , chemistry , nanotechnology , molecular dynamics , topology (electrical circuits) , materials science , molecule , biology , gene , biochemistry , computational chemistry , organic chemistry , mathematics , combinatorics
Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology‐encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.