# 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.

## Key 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.