Tuning the Topological Landscape of DNA‐Cyclodextrin Nanocomplexes by Molecular Design

Here we report original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates. 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, which 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 to 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 templation. Since the stability of the dimers depends on the protonation state of the polycationic clusters, the co-aggregates display pH responsiveness, which facilitates endosomal scape 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 non-viral gene delivery systems uniquely suited for optimization schemes.