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A collaboration of scientists at the University of Manchester and the University of Birmingham have explored a more effective and less toxic way of delivering genetic material into cells, a challenge central to areas such as gene therapy, biotechnology and genome editing.

This new technique utilises self鈥�assembling polymer carriers for gene delivery, improving effectiveness and reducing the toxicity to cells over existing techniques in lab tests. These advances rely on safe and efficient methods for delivering gene鈥慹diting tools into cells, which is a key bottleneck in enabling widespread application. Improving upon existing gene delivery methods has become essential to enable these developments and allow more effective transfection.

The process of introducing DNA or RNA into cells to change gene expression, can be achieved using viral or non鈥�viral vectors. While viral vectors are powerful, they raise safety and manufacturing concerns, driving intense interest in the development of safer, non鈥�viral alternatives. Transfection, using polymeric carriers or lipid nanoparticles to deliver genetic material, is a key non鈥�viral strategy. However current systems often struggle to balance efficiency and toxicity. In order to develop polymer systems for molecular delivery applications, more advanced polymer systems need to be developed and screened.

In research published in ACS Materials Letters, the team demonstrates that polyplexes produced via Polymerization鈥�Induced Electrostatic Self鈥�Assembly (PIESA) offer a more effective and versatile route to gene delivery than conventional produced polymeric polyplexes. Polyplexes are formed when positively charged polymers bind to negatively charged DNA or RNA, creating nanoscale complexes that can enable genetic material to enter cells. Traditionally, polyplexes are prepared using pre-synthesised polymers which are then mixed with DNA or RNA. However, this post鈥�assembly step can lead to instability and increased cell toxicity, often limiting the size of genetic payloads that can be delivered effectively.

PIESA using PET鈥�RAFT (Photoinduced Electron/Energy Transfer Reversible Addition-Fragmentation Chain-Transfer) polymerisation overcomes these limitations by driving electrostatic self鈥�assembly during polymer growth. As the polymer forms, it binds to the genetic material, producing polyplexes with controlled sizes, structures, and physicochemical properties. By using a 鈥渙ne鈥�pot鈥� approach to produce polyplexes, the need for complex post鈥�processing is avoided, resulting in improved consistency and facilitating high鈥�throughput screening of formulations

The study shows that PIESA鈥�derived polyplexes are less toxic to cells than their conventionally assembled counterparts and act as more effective gene delivery vehicles in transfection trials, achieving higher gene expression while preserving cell viability.

Transitioning to advanced synthesis and assembly strategies such as PIESA could open the door to the next鈥�generation of non鈥�viral gene delivery systems, with improved transfection, broader formulation windows, and reduced cell toxicity.

Dr Lee Fielding added 鈥淭his approach potentially opens up a more reliable and scalable route to non鈥憊iral gene delivery. By innovating in how polyplexes can be prepared and screened for improved efficiency, while reducing toxicity, we hope it will help accelerate the development of gene delivery technologies and make them more accessible across biomedical research and clinical applications."