Trifaceted Mickey Mouse Amphiphiles for Programmable Self‐Assembly, DNA Complexation and Organ‐Selective Gene Delivery

Abstract

Instilling segregated cationic and lipophilic domains with an angular disposition in a trehalose-based trifaceted macrocyclic scaffold allows engineering patchy molecular nanoparticles leveraging directional interactions that emulate those controlling self-assembling processes in viral capsids. The resulting trilobular amphiphilic derivatives, featuring a Mickey Mouse architecture, can electrostatically interact with plasmid DNA (pDNA) and further engage in hydrophobic contacts to promote condensation into transfectious nanocomplexes. Notably, the topology and internal structure of the cyclooligosaccharide/pDNA co-assemblies can be molded by fine-tuning the valency and characteristics of the cationic and lipophilic patches, which strongly impacts the transfection efficacy in vitro and in vivo. Outstanding organ selectivities can then be programmed with no need of incorporating a biorecognizable motif in the formulation. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes by making cyclooligosaccharide patchiness the focus.

Trehalose-polyamine/DNA nanocomplexes: impact of vector architecture on cell and organ transfection selectivity

“…34 Further on, α,α'-trehalose-based macrocycles (cyclotrehalans, CTs) were found to undergo co-assembly with plasmid DNA (pDNA) to afford transfectious nanocomplexes (CTplexes) with organ-selective gene delivery capabilities. 35…”

Extending the Scope of the C-Functionalization of Cyclam via Copper(I)-Catalyzed Alkyne–Azide Cycloaddition to Bifunctional Chelators of Interest

“…Finally, we focused on the development of polycationic amphiphilic trehalose derivatives with Siamese and Janus-macrocyclic structure (cyclotrehalans, CTs) . These terms refer specifically to α,α′-trehalose-based amphiphiles, which are symmetrical , or cyclic structures formed from α,α′-trehalose (a nonreducing sugar composed of two linked glucose molecules). These structures have been studied for their ability to undergo coassembly with plasmid DNA (pDNA) to form transfection complexes.…”

Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host‐Guest Dimerization of Cyclooligosaccharide Star Polycations

“…We recently reported that macrocycles built from the disaccharide α , α ’‐trehalose (cyclotrehalans, CTs) represent an appealing alternative to CDs. [ 12 ] Differently from CDs, CTs depict a convex inner hydrophobic cavity flanked by secondary hydroxyls that project from concave faces. [ 13 ] In principle, this architecture must facilitate the access of size‐fitting guests to the cavity even if relatively bulky O ‐substituents are present.…”