Synthesis of Multi-Silencing Polymerized RNA Nanoparticles for Enhanced Cardiac Transdifferentiation via Microneedle Delivery

My research aims to advance drug delivery by developing multi-silencing polymerized RNA nanoparticles (Multi-R-NPs) for customized treatments across a wide range of diseases, using engineered microneedles to enhance efficacy. This versatile platform can be adapted for applications such as stem cell differentiation and biosensing, with immediate potential to treat fibrotic diseases like cardiac and pulmonary fibrosis, reducing preventable mortality and improving patient quality of life. Therapeutic transdifferentiation of cardiac fibroblasts into induced cardiomyocyte-like cells could address the limitations of conventional cardiac fibrosis therapies, which typically only manage symptoms and do not prevent the progression of the disease. However, current transdifferentiation strategies face challenges such as low transfection efficiency, uncontrolled gene expressions, and immune responses to viral vectors. This proposal aims to develop multi-silencing polymerized RNA nanoparticles (Multi-R-NPs) through rolling circle transcription (RCT) to enable unique combination therapies that synergize multiple nucleic acid therapeutics. Moreover, to minimize the side effects of untargeted delivery and overcome barriers to cardiac delivery, we will use microneedles to enable local Multi-R-NP transfection. I anticipate that combining two state-of-the-art technologies, RCT and microneedles, will enable the delivery of synergistic nucleic acid therapeutics and promote more optimal cardiac repair through efficient transdifferentiation. During my fellowship at the University of Oxford in Professor Dame Molly Stevens’ lab, I will apply precise control polymerization of therapeutic RNAs and formulate multi-layered polyplex structures. The strong collaborative networks with the British Heart Foundation Centre for Research Excellence and the co-supervision of Prof. Stevens and Prof. Riley will bring out the full translational potential of this project.