pH-Responsive Natural Polymeric Gene Delivery Shielding System Based on Dynamic Covalent Chemistry

Area of Science:

• Biomaterials Science
• Nanotechnology
• Gene Therapy

Background:

• Gene delivery systems face challenges balancing transfection efficiency and stability.
• Poly(ethyleneimine) (PEI)/DNA polyplexes are effective gene carriers but can cause toxicity and instability.
• pH-responsive materials offer potential for targeted drug and gene delivery.

Purpose of the Study:

• To develop a pH-responsive shielding system for PEI/DNA polyplexes using aldehyde-bearing dextran derivatives (ODEX/FDEX).
• To improve the stability of gene carriers during circulation and enhance targeted delivery to tumor sites.
• To address the dilemma between high transfection efficiency and carrier stability in gene therapy.

Main Methods:

• Synthesized aldehyde-bearing dextran derivatives (ODEX/FDEX).
• Formulated pH-responsive polyplexes by forming Schiff base bonds between dextran derivatives and PEI.
• Evaluated nanoparticle size, ζ-potential, stability, cellular uptake, and gene transfection efficiency in vitro and in vivo.

Main Results:

• The ODEX/FDEX system effectively shielded PEI/DNA polyplexes via pH-sensitive Schiff base bonds.
• Shielded polyplexes exhibited reduced size and ζ-potential, enhancing stability in neutral environments.
• The system demonstrated triggered polyplex release and enhanced gene expression in acidic tumor environments.
• FDEX/PEI/DNA nanoparticles showed superior in vitro cellular uptake and transfection efficiency, and higher in vivo tumor gene expression compared to ODEX analogues.

Conclusions:

• The developed pH-responsive system using aldehyde-bearing dextran derivatives is a promising strategy for targeted gene therapy.
• This approach effectively overcomes the limitations of traditional gene carriers by enhancing stability and targeted delivery.
• The FDEX/PEI/DNA nanoparticles show significant potential for improving cancer treatment outcomes.