Transporting Stable RNA Across the Blood-Brain Barrier for On-Demand Translation

PROJECT ABSTRACT While modern medicine has seen many advances that have improved human health over the last century, most medications available to the public do not act on the cause of disease, mainly focusing on alleviating symptoms associated with downstream effects. The overarching goal of my research program is to develop nanoparticles with pathologically responsive chemistries to enable the targeted delivery of disease-modifying biologic agents. One such focus is on the use of RNA-based therapies. Compared to traditional methods of altering gene or protein expression that involve editing or modification, RNA-based therapies offer several advantages, including a lower risk of off-target genetic mutations, temporary and controlled therapeutic gene expression, and a shorter production time, which facilitates rapid responses to various emerging health challenges. However, the translatability of RNA-based therapeutics relies on some sort of delivery vehicle or modification to assist in biologic transport, like a nanoparticle. Although delivery of nucleic acids in lipid nanoparticles (LNPs) has been successful, the effect is transient due to the transient nature and RNAse degradability of nucleic acids, which means multiple injections are often required to receive a lasting protective effect and therapeutic effects are minimized. Furthermore, LNPs notoriously traffic payloads to the liver, which does not enable their use in alternative tissue targets. In this proposal, we lay out a high-risk, high-reward approach to 1. Increase the stability of RNA in vivo, 2. Control the timing of RNA release and protein translation, and 3. Enable the delivery of RNA- based therapeutics into the brain, therefore addressing the current translational concerns and extending RNA therapy to tissues that are difficult to reach using polymer-based nanoparticles, called polymersomes (Figure 1). Furthermore, although our initial focus is on mRNA, our approach could be widely applied to other negatively charged RNAs. Stimuli-responsive coacervated mRNA will be encapsulated in polymersomes and delivered across the blood-brain barrier, enabling RNA translation on demand in brain tissue for the first time.