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

Area of Science:

• Biomaterials Science
• Nanotechnology
• Molecular Medicine

Background:

• Developing efficient and selective nucleic acid delivery vectors is crucial for gene therapy.
• Existing cyclodextrin-based systems often lack precise control over self-assembly and targeting.
• Novel molecular architectures are needed to overcome current delivery limitations.

Purpose of the Study:

• To introduce and characterize a new class of cyclodextrin-based geometrically frustrated amphiphiles (GFAs) for nucleic acid delivery.
• To investigate the self-assembly properties and DNA complexation behavior of GFAs.
• To evaluate the in vitro and in vivo transfection efficiency and organ targeting selectivity of GFA-nucleic acid nanocomplexes.

Main Methods:

• Synthesis and characterization of geometrically frustrated amphiphiles (GFAs) based on β-cyclodextrin.
• Investigation of pH-dependent self-assembly of GFAs into vesicles and molecular forms.
• Formation and characterization of GFA-plasmid DNA (pDNA) nanocomplexes, including topological and internal order analysis.
• In vitro cell transfection studies to assess delivery efficiency.
• In vivo studies to determine organ targeting outcomes.

Main Results:

• GFAs exhibit unique functional group distribution, enabling access to monodisperse variants.
• pH-dependent self-assembly of GFAs into different structures (bilayered vesicles, monolayered vesicles, individual molecules).
• GFA-pDNA nanocomplexes show tunable topological and internal order, with preferred pupa-like arrangements.
• Significant differences in in vitro transfection performance and distinct in vivo organ targeting (liver, lung, kidney, spleen) were observed based on GFA architecture.

Conclusions:

• Cyclodextrin-based GFAs represent a promising new class of molecular vectors for nucleic acid delivery.
• The molecular architecture of GFAs allows for fine-tuning of self-assembly and DNA complexation.
• GFAs demonstrate potential for achieving selective cell and organ transfection, paving the way for targeted gene delivery applications.