Gene Delivery Mediated by Backbone-Degradable RAFT Copolymers

TL;DR

Scientists created biocompatible polymers that can deliver genes efficiently without causing toxicity.

Contribution

The study introduces backbone-degradable cationic copolymers that improve gene delivery efficiency and biocompatibility.

Findings

Degradable copolymers increased transfection efficiency 10-fold at low N/P ratios.

The polymers maintained low cytotoxicity while enhancing gene delivery performance.

Degradability is hypothesized to improve payload release in the cytosol.

Abstract

Cationic polymers present an attractive platform for gene delivery. However, these highly charged macromolecules can also lead to cytotoxicity. Therefore, there is a strong unmet need to develop efficacious polymeric gene delivery vehicles with high biocompatibility. Here, we leverage recent advances in polymer chemistry to develop backbone-degradable cationic copolymers and evaluate their potential as gene delivery vehicles. Specifically, polycations were prepared via copolymerization with macrocyclic allylic sulfides, which can participate in PET-RAFT polymerization via radical ring-opening cascade copolymerization to install degradable backbone segments. A polymer library with varying degradabilities was prepared and evaluated using a model GFP plasmid to transfect U-2 OS cells. Incorporation of degradable groups into the copolymer backbone improved transfection efficiency 10-fold at low amine/phosphate (N/P) ratios without increasing cytotoxicity, thereby enhancing their value as gene delivery carriers. We hypothesize that degradability may enhance the complex’s disassembly kinetics in the cytosol, enabling more efficient payload release.

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