Expanding the design space of polyelectrolyte complex micelles

PROJECT SUMMARY Polyelectrolyte complex micelles (PCMs) are a unique class of self-assembled nanoparticles that form with a core of associated polycations and polyanions surrounded by a neutral corona. The hydrated nature and structural and chemical versatility make PCMs an attractive system for delivering hydrophilic payloads while controlling carrier size and stability. While recent studies have shown PCMs are effective at delivering nucleic acids, the design process has largely been trial-and-error to this point with few systematic studies focused on defining and predicting PCM properties and behavior in physiological conditions. By leveraging polymer design, controlled self- assembly, and materials characterization techniques, the goal of this proposal, and of our research group, is to develop design rules quantifying the relationships between polymer and nucleic acid structure and PCM assembly, physical properties, delivery, and dynamic behavior. We will use small-angle X-ray scattering, electron microscopy, and fluorescence imaging to accomplish three broad goals: 1) develop structure-property relationships based on polymer and nucleic acid structure, chemistry, size, and charge density, 2) quantify the effect of PCM component structure on cellular uptake and cargo release, and 3) uncover the mechanism, kinetics, and factors that control nucleic acid exchange between PCMs. As each area progresses we will use computational methods to analyze our vast PCM characterization database and establish the scaling laws and relationships driving PCM assembly and function. The proposed work will build the foundation for a new class of PCMs with predictive properties tailored to each treatment, aligning our lab goals with the overarching mission of NIGMS.