Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene...

Area of Science:

• Biomaterials Science
• Nanotechnology
• Gene Therapy

Background:

• Systemic nonviral gene delivery faces challenges in achieving prolonged circulation and efficient tissue transfection.
• Developing effective nonviral gene vectors is crucial for in vivo applications.

Purpose of the Study:

• To construct and evaluate novel rod-shaped ternary polyplex micelles (TPMs) for enhanced in vivo gene delivery.
• To investigate the temperature-responsive properties and performance of TPMs compared to binary polyplex micelles (BPMs).

Main Methods:

• TPMs were formed by complexing mixed block copolymers (PEG-b-PAsp(DET) and PNIPAM-b-PAsp(DET)) with plasmid DNA (pDNA).
• Temperature-responsive formation of a hydrophobic intermediate layer was induced by increasing temperature to ~37 °C.
• In vitro and in vivo studies assessed pDNA condensation, nuclease resistance, cellular uptake, endosomal escape, blood circulation time, tumor accumulation, gene expression, and anti-tumor efficacy.

Main Results:

• TPMs condensed pDNA into a more compact structure than BPMs, showing enhanced nuclease resistance.
• TPMs exhibited efficient cellular uptake and endosomal escape, leading to enhanced in vitro gene transfection.
• In vivo studies showed prolonged blood circulation, high tumor accumulation, and effective gene expression in tumor tissues.
• TPMs loaded with anti-angiogenic pDNA significantly suppressed tumor growth in H22 tumor-bearing mice.

Conclusions:

• TPMs possess a unique structure with PEG shells and an engineered intermediate barrier, facilitating effective gene delivery.
• These temperature-responsive TPMs show great potential as systemic nonviral gene vectors for cancer gene therapy.