Supramolecular Aggregate as a High-Efficiency Gene Carrier Mediated with Optimized Assembly Structure

Area of Science:

• Biomaterials Science
• Nanotechnology
• Cancer Therapy

Background:

• Developing safe and efficient gene carriers is crucial for cancer gene therapy.
• Existing polymer carriers often face a trade-off between transfection efficiency and cytotoxicity.
• Complex polymer synthesis and high molecular weights contribute to these challenges.

Purpose of the Study:

• To propose a supramolecular strategy for constructing gene delivery aggregates from small molecules.
• To investigate the relationship between supramolecular assembly structure and gene delivery capability.
• To develop a gene carrier with high efficiency and low toxicity for cancer therapy.

Main Methods:

• Synthesis of PEI-conjugating β-cyclodextrin (PEI-6-CD and PEI-2-CD) and assembly with ferrocene-ended polyethylene glycol (PEG-Fc).
• Utilizing supramolecular inclusion to form aggregates for delivering MMP-9 shRNA plasmid.
• In vitro and in vivo assays to evaluate transfection efficiency, cytotoxicity, gene silencing, and anti-tumor effects in MCF-7 cancer models.

Main Results:

• PEI-2-CD based supramolecular aggregates demonstrated higher gene transfection efficiency compared to PEI-25k.
• These aggregates exhibited significantly lower cytotoxicity due to their small/low molecular nature.
• Effective delivery of MMP-9 shRNA plasmid led to downregulated MMP-9 expression, inducing cancer cell apoptosis and inhibiting tumor growth in vivo.
• Optimized host/guest molar ratios and supramolecular architecture enhanced gene delivery performance.

Conclusions:

• Supramolecular aggregates offer a promising alternative gene carrier for cancer gene therapy.
• This strategy provides a new paradigm for designing gene carriers by rationally modulating supramolecular architectures.
• The developed system shows potential for effective and safe cancer treatment by targeting MMP-9.