Plasmid‐Templated Control of DNA–Cyclodextrin Nanoparticle Morphology through Molecular Vector Design for Effective Gene Delivery

Abstract

Engineering self-assembled superstructures through complexation of plasmid DNA (pDNA) and single-isomer nanometric size macromolecules (molecular nanoparticles) is a promising strategy for gene delivery. Notably, the functionality and overall architecture of the vector can be precisely molded at the atomic level by chemical tailoring, thereby enabling unprecedented opportunities for structure/self-assembling/pDNA delivery relationship studies. Beyond this notion, by judiciously preorganizing the functional elements in cyclodextrin (CD)-based molecular nanoparticles through covalent dimerization, here we demonstrate that the morphology of the resulting nanocomplexes (CDplexes) can be tuned, from spherical to ellipsoidal, rod-type, or worm-like nanoparticles, which makes it possible to gain understanding of their shape-dependent transfection properties. The experimental findings are in agreement with a shift from chelate to cross-linking interactions on going from primary-face- to secondary-face-linked CD dimers, the pDNA partner acting as an active payload and as a template. Most interestingly, the transfection efficiency in different cells was shown to be differently impacted by modifications of the CDplex morphology, which has led to the identification of an optimal prototype for tissue-selective DNA delivery to the spleen in vivo.

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

“…Micellar or vesicular aggregates could then form, depending on the hydrophilic/‐phobic balance, which could be tuned by modifying the CD size (α‐ or β‐CD) or the number of primary amine groups per monosaccharide subunit (one or two), thereby widening the opportunities to modulate the interactions with nucleic acids, and thus, the topologies of the corresponding nanocomplexes. To test this idea, we designed a library of 16 compounds ( 1 – 8 for α‐CD and 9 – 16 for β‐CD derivatives; Scheme 1), which, in addition to the “clipped” hybrids, includes the corresponding per( O ‐2, O ‐3)methyl α‐ and β‐CD controls ( 1 , 5 , and 9 , [23] and 13 , [16a] respectively; see the Supporting Information for details of their synthesis and physicochemical characterization).…”

Hydrogen‐Bond Cyclization Programming of Ultrasensitive Esters and Its Application in Gene Delivery

“…Nonviralg ene delivery systemsa re usually implementedw ith positivelyc hargedm aterials, such as branched PEI 25k and the polyamidoamine dendrimer,owing to their eminentgene complexing ability, [1][2][3][4][5][6][7][8][9][10] but the inability to release genes of these materials reducest ransfection efficiency. Ad isulfide moiety was introduced into these materials to give them the ability to releaseg enes in cells.…”

Trehalose-based Siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

“…1A); however, keeping diastereomeric purity can be significantly demanding. 7 This problem is largely mitigated for the cationic lipid dimers generically termed gemini surfactants, 8 the smallest representatives of multivalent amphiphiles (Fig. 1B).…”

“…9 Most importantly, the topological properties and stability of multivalent and geminibased supramolecular aggregates exhibit a strong dependence on vector structure and local pH, enabling control over cell uptake and cargo release. [7][8][9] Here we report that the disaccharide a,a 0 -trehalose, a C 2 -symmetrical glucose dimer, can be engineered through modular ''click'' strategies to access ''Siamese twin'' surfactants amalgamating the advantages of gemini and facial amphiphilicity for efficient DNA nanocomplexation and delivery in vitro and in vivo (Fig. 1C).…”

“…Multivalent facial amphiphiles, including gemini surfactants, experience increasing electrostatic repulsions upon acidification, resulting in destabilization of the pDNA co-assemblies. 7,8 Individual components can then interact with the endosome membrane, provoking disruption and DNA leakage into the cytoplasm. The new hybrid vectors 6-10 were anticipated to benefit from this mechanism.…”