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.
Highlights
Surface anisotropy has proven to be vital in biological systems
CTs can potentially be constructed from differently functionalized building blocks, resulting in anisotropically-faceted architectures. This notion was first realized for the simplest CT2 core: perfect Janus MNPs featuring cationic (C) and lipophilic (L) halves were elaborated that formed multilamellar transfectious nanocomplexes (CTplexes) with plasmid DNA (Figure 2A).[13]
One can anticipate that going from the Janus-type CT2 pattern (Figure 2A) to the C1L2 trilobular CT3 organization (Figure 2B, left) would roughly multiply by two the volume of the hydrophobic area in the corresponding amphiphiles
Summary
Surface anisotropy has proven to be vital in biological systems. An example is the well-regulated structural control seen in virus capsids, which stems from the overall shape of the folded protein, the arrangement of hydrophobic areas on the protein surface and the distribution of charged residues, altogether setting up the spread of disease by self-assembly of viral particles in vivo.[1]. C. Ortiz Mellet Department of Organic Chemistry, Faculty of Chemistry University of Sevilla C/ Prof García González 1, 41012, Sevilla (Spain) E-mail: mellet@us.es
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