10171274Development of long lasting RNAs for in vivo T-cell engineering in CancerClosedFast Start ResponseInnovate UKCambridge RNA Technologies is developing a new generation of RNA molecules designed to support safer and more durable genetic treatments and therapeutic engineering of cells. These engineered "long-term RNAs" (ltRNAs) aim to enable _in vivo_ delivery of therapeutic instructions to cells without permanently modifying the cell's DNA and the associated risks. DNA-based approaches can offer long-lasting effects, but also carry risks such as unwanted changes to the genome, which may raise safety concerns, particularly for patients with chronic but non-life-threatening conditions. On the other hand, RNA-based approaches are much safer because they don't integrate into the genome, but are limited by how quickly RNA breaks down in the cells, often within a couple of days. Recent innovations like circular RNA and self-amplifying RNA offer partial solutions, but challenges remain. Circular RNAs only have a modestly extended duration and self-amplifying RNAs, for example, can trigger inflammation or toxicity, limiting their use to certain vaccines or short-term treatments e.g. delivery of inflammatory factors in cancer. This project addresses the need for a safer, longer-lasting, and more controllable approach. By developing RNAs with extended stability inside cells, CRT aims to deliver the benefits of durable expression, without the risks of permanent genome editing. The technology is designed to be compatible with established delivery systems like lipid nanoparticles (LNPs), which were widely used in mRNA COVID-19 vaccines with various enhancements for cell type specific delivery available. If successful, this work could open the door to a new class of therapies that are safer, more accessible, and more scalable. These could support progress in cancer treatment, autoimmune diseases, and other areas where precision, durability, and safety are all critical. The project also contributes to the UK's position as a global leader in RNA therapeutics and engineering biology