Trifaceted Mickey Mouse Amphiphiles for Programmable Self-Assembly, DNA Complexation and Organ-Selective Gene...

Area of Science:

• Supramolecular Chemistry
• Nanotechnology
• Biomaterials Science

Background:

• Viral capsids utilize directional interactions for self-assembly, offering a model for synthetic systems.
• Nonviral gene delivery systems require efficient methods for condensing genetic material and achieving targeted delivery.

Purpose of the Study:

• To engineer novel patchy molecular nanoparticles using a trehalose-based scaffold.
• To investigate the self-assembly of these nanoparticles with plasmid DNA (pDNA) for gene delivery.
• To explore the impact of nanoparticle architecture on transfection efficacy and organ selectivity.

Main Methods:

• Design and synthesis of trifaceted macrocyclic scaffolds with segregated cationic and lipophilic domains.
• Formation of trilobular amphiphilic derivatives with a 'Mickey Mouse' architecture.
• Co-assembly with plasmid DNA (pDNA) to form transfectious nanocomplexes.
• In vitro and in vivo evaluation of transfection efficacy and organ selectivity.

Main Results:

• The engineered nanoparticles successfully condensed pDNA through electrostatic and hydrophobic interactions.
• Nanoparticle topology and internal structure were tunable by modifying patch valency and characteristics.
• Transfection efficacy in vitro and in vivo was significantly impacted by the co-assembly's structure.
• Achieved organ selectivity without incorporating specific biorecognizable motifs.

Conclusions:

• A versatile strategy for constructing synthetic, monodisperse nonviral gene delivery systems was developed.
• Cyclooligosaccharide patchiness is a key factor for optimizing gene delivery systems.
• The engineered nanoparticles offer a promising platform for advanced gene therapy applications.