Structural Design of Therapeutic Nanoparticles

Developing experimental design rules through physical characterization

Non-viral delivery of therapeutic nucleic acids is a critical challenge for nanomedicine, one that has a heightened spotlight with the recent development of RNA COVID-19 vaccines and primed to conquer more devastating diseases. Therapeutic nucleic acids including plasmid DNA, microRNA, messenger RNA, and CRISPR-Cas9 offer the immense potential of altering gene expression to cure disease, but the major hurdle of delivery stands in the way. Designing nanoparticles for delivery is crucial, as the size and chemical composition of DNA and RNA limit transfection and are susceptible to enzymatic degradation. 

We have developed precise size scaling laws and exposed stability dependencies on molecular structure, showing that polymer and nucleic acid design control nanoparticle morphology, size, and stability; all crucial design parameters that affect stealth, biodistribution, and cell uptake. However, the current state of structure-property relationships for nucleic acid nanoparticles is still limited and falls short of predicting nanoparticle function in complex biological environments.

Translating structure-property relationships to clinical conditions is an unmet need. Designing for encapsulation, transport, targeting, and release requires extensive material characterization and a thorough understanding of the molecular nuances of polymer interactions. We build nucleic acid delivery systems with programmable targeting and controlled release capabilities by translating rigorous physical characterization to clinical applications. 

Design rules for nucleic acid nanoparticles. Systematic characterization of nucleic acid nanoparticles allows us to establish a programmable structural design approach.  This will be applied to multiple classes of nanoparticles, starting with polyelectrolyte complex micelles and continuing with lipid and amphiphilic polymer assemblies. The full path of delivery will be considered including stability, stealth, biodistribution, cell-surface targeting, internalization via endocytosis, endosomal escape, and release into the cytosol for gene silencing or translation.

With this approach, we study the assembly and behavior of polyelectrolyte complex micelles (PCMs), lipid nanoparticles (LNPs), and polymersomes.