Reducible polyrotaxane-based pseudo-comb polycations via consecutive ATRP processes for gene delivery

Area of Science:

• Materials Science
• Polymer Chemistry
• Biotechnology

Background:

• Supramolecular cyclodextrin polyrotaxanes (PR) offer unique flexible properties.
• Developing efficient and safe non-viral gene delivery vectors remains a challenge.

Purpose of the Study:

• To synthesize novel bioreducible polyrotaxane-based cationic polymers for enhanced gene delivery.
• To evaluate the gene delivery performance, including DNA condensation, cell uptake, and transfection efficiency.

Main Methods:

• Preparation of bioreducible PR-based cationic block copolymer (SS-PR) via ATRP.
• Synthesis of pseudo-comb polycations (SS-PR-pDM) with varying molecular weights using SS-PR as a macroinitiator.
• Assessment of pDNA condensation, cytotoxicity, cell internalization, and gene transfection efficiency.

Main Results:

• SS-PR-pDM demonstrated enhanced pDNA-condensing ability and low toxicity.
• Pseudo-comb SS-PR-pDM showed significantly higher cell internalization rates (88% vs. 77%) and EGFP transfection efficiency (44% vs. 22%) compared to SS-PR.
• Disulfide linkages enabled disassembly under reductive stimuli, facilitating pDNA release and nuclear entry.

Conclusions:

• Grafting cationic side chains onto bioreducible polyrotaxane backbones via ATRP is an effective strategy for creating advanced supramolecular polycations.
• The synthesized SS-PR-pDM polycations show great potential as efficient and safe non-viral gene delivery vectors.
• The bioreducible nature and pseudo-comb architecture contribute to improved gene delivery outcomes.