β-Cyclodextrin-based geometrically frustrated amphiphiles as one-component, cell-specific and organ-specific nucleic...

We introduce an innovative β-cyclodextrin (βCD)-prototype for delivering nucleic acids: "geometrically frustrated amphiphiles (GFAs)." GFAs are designed with cationic centers evenly distributed across the primary O6 and secondary O2 positions of the βCD scaffold, while hydrophobic tails are anchored at the seven O3 positions. Such distribution of functional elements differs from Janus-type architectures and enlarges the capacity for accessing strictly monodisperse variants. Changes at the molecular level can then be correlated with preferred self-assembly and plasmid DNA (pDNA) co-assembly behaviors. Specifically, GFAs undergo pH-dependent transition between bilayered to monolayered vesicles or individual molecules. GFA-pDNA nanocomplexes exhibit topological and internal order characteristics that are also a function of the GFA molecular architecture. Notably, adjusting the pK_a of the cationic heads and the hydrophilic-hydrophobic balance, pupa-like arrangements implying axial alignments of GFA units flanked by quasi-parallel pDNA segments are preferred. In vitro cell transfection studies revealed remarkable differences in relative performances, which corresponded to distinct organ targeting outcomes in vivo. This allowed for preferential delivery to the liver and lung, kidney or spleen. The results collectively highlight cyclodextrin-based GFAs as a promising class of molecular vectors capable of finely tuning cell and organ transfection selectivity.