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

2021; Wiley; Volume: 27; Issue: 36 Linguagem: Inglês

10.1002/chem.202100832

1521-3765

Ana I. Carbajo‐Gordillo, Manuel González‐Cuesta, José L. Jiménez Blanco, Juan M. Benito, María L. Santana‐Armas, Thais Carmona, Christophe Di Giorgio, Cédric Przybylski, Carmen Ortiz Mellet, Conchita Tros de Ilarduya, Francisco Mendicuti, José M. Garcı́a Fernández,

Supramolecular Self-Assembly in Materials

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.