Diffuse Midline Glioma (DMG) is a fast-growing and incurable paediatric brain tumour with a life expectancy of <1 year. New treatments using Chimeric Antigen Receptor (CAR)-modified T cells are being trialled clinically and have shown early promise in DMG, providing temporal reductions in tumour growth. CAR T cells are a living therapeutic that kill cancers cells by recognising specific targets on their cell surface. However, current manufacturing of CAR T cells is a complex and lengthy process that is incompatible with the aggressiveness of DMG. Neurotoxicity arising from the uncontrollable effects and indefinite duration of CAR T cell therapy is an additional obstacle that must be addressed to improve the clinical success and implementability of this approach in DMG. To overcome these obstacles, we focus our research on developing innovative immunotherapeutic technologies where we use ‘ready-made’ messenger RNA nanoparticles (mRNA-NPs) to reprogram circulating T cells directly in vivo to drive rapid & controlled immune responses against the rapidly proliferating DMG tumours. This strategy bypasses the current need to extract and modify ex vivo the T cells whilst offering the advantages in accessibility and convenience of an off-the-shelf drug. This presentation will showcase our research on in vivo CAR-T cell development, using mRNA-NPs, including the exploration of different strategies for mRNA-NP targeting to T cells and in vivo testing of these therapeutics in tumour-engrafted mice. Additional immune-reprogramming strategies currently being explored in our mRNA immunotherapy program will also be discussed, demonstrating the vast applicability of mRNA technologies in the management of brain tumours.