Bioinspired, Guanidinium, and Indole Modified Poly(glycidyl ether)s as Highly Efficient Vectors for Polyplex‐Mediated Gene Delivery

TL;DR

Scientists designed new polymers for gene delivery that balance hydrophilic and hydrophobic properties to improve efficiency and safety.

Contribution

A modular approach to create functionalized poly(glycidyl ether)s with tunable hydrophilic-hydrophobic balance for gene delivery.

Findings

Polymers with moderate indole content achieved transfection efficiencies exceeding poly(ethylene imine).

Hydrophobicity strongly influences transfection efficiency in CHO-K1 cells.

Stable DNA polyplexes were formed with all polymers, protecting DNA from degradation.

Abstract

Allyl glycidyl ether and 2‐methoxyethyl glycidyl ether were copolymerized via anionic ring‐opening polymerization and subsequently functionalized with guanidinium and indole groups through a post‐polymerization thiol‐ene reaction. This modular approach yielded eight polymers with systematically varied hydrophilic‐hydrophobic balance, carrying 50–92 mol% guanidinium and 0–22 mol% indole. The polymers featured molar masses between 10.1 and 15.7 kg/mol with a dispersity of around 1.3. Polyplexes were formulated using plasmid DNA and characterized with respect to their physicochemical properties including DNA binding affinity, surface charge, and particle size as well as their transfection efficiencies and polymer in vitro cytotoxicity. All polymers were able to form stable complexes and protected their cargo against enzymatic degradation. An additional hydrophilic monomer did not influence physicochemical characteristics, but increased polymer cytotoxicity. Transfection studies in CHO‐K1 cells revealed a strong dependence on polymer hydrophobicity: polymers with medium indole content outperformed both more hydrophilic and more hydrophobic analogues, reaching efficiencies above the gold standard poly(ethylene imine). These results underline the critical role of balancing hydrophilic and hydrophobic groups in side‐chain functionalized poly(glycidyl ether)s for safe and effective gene delivery.

Guanidinium‐ and indole‐functionalized poly(glycidyl ether)s were developed as non‐viral gene delivery vectors with tunable hydrophilic–hydrophobic balance. All polymers formed stable DNA polyplexes, while moderate indole content yielded the highest transfection efficiency at low N/P ratios. The study highlights hydrophobic balance as a key design principle for efficient and safe polymer‐based gene delivery.

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