Although it is known that the structure of lipid nanoparticles can be engineered to augment stability and transfection, the broader chemical and structural diversity of polymeric RNA delivery materials remains largely untapped. We will use high throughput synthesis, formulation, and characterization methods to generate ML-interpretable datasets that evolve transfection formulations with desirable properties for specific applications. High performing formulations will form the basis for more detailed structure-function studies using fluorescence correlation spectroscopy (FCS), small angle scattering (SAXS/SANS), and molecular dynamics modeling (MD).

While innate immunogenicity is a well documented barrier to therapeutic RNA applications, we are just beginning to understand how delivery formulations modulate human innate responses to transfection. We use human skin explant cultures and will use lymphoid organoid models to study connections between formulation chemistry, endocytosis, and danger sensing pathways to engineer more effective RNA vaccines and therapeutics with fewer side effects.

Targeting the delivery of immunomodulatory drugs can engineer immune response that alter the effects of co-delivered therapeutics. For example, we have shown that lymph node targeted STING agonism extended saRNA transfection from polymeric nanoparticles by dampening cytotoxic T cell responses. Where and when should drugs be delivered to augment RNA function? How can we leverage or inhibit innate responses for therapeutic benefit?