Precision RNA delivery technology to unlock new potentials in CNS biology

PROJECT SUMMARY/ABSTRACT The project seeks to establish a versatile platform for RNA delivery, specifically tailored for the central nervous system (CNS). This platform is designed to integrate three pivotal capabilities that are currently unmet in the field: high-efficiency delivery, precise cell-specific targeting, and minimal cellular disruption. To achieve this ambitious goal, our innovation is to combine RNA-encapsulating capsids with endosomal escape peptides that mediate high levels of cell penetration without harming cells. The first specific aim will focus on the engineering of encapsulation capsids that release their RNA cargo upon cytosolic entry. The second aim is dedicated to capsid surface engineering to achieve controlled, cell-specific endocytosis. The third aim extends the investigation to in vivo contexts, validating the technology against established RNA/lipid formulations through precision-guided injections in cortical and spinal tissues. The success will be measured by the system's efficiency, selectivity, and its ability to deliver without inducing cytotoxic effects or cellular stress. Underpinning this endeavor, the research incorporates a suite of quantitative and mechanistic assays designed to rigorously evaluate and refine the delivery system. The fulfillment of these aims will result in a transformative RNA delivery system, conferring researchers with unprecedented control and specificity in modulating gene expression within the CNS. This delivery platform is adaptable to a range of research needs and designed for easy adoption, setting the stage for significant advancements in basic neuroscience research and the development of novel therapeutic strategies for neurological disorders.