Relating chemical and physical properties of oligonucleotide polyelectrolyte complex micelles

Statement of Purpose: Developing effective non-viral methods for delivery of nucleic acids and other macromolecular therapeutics is one of the most pressing challenges for nanomedicine and polymer science [1]. The potential power of engineered nucleic acids as therapeutic agents is severely limited by the difficulty of overcoming the physical and biological barriers to using them as practical drugs. Polyelectrolyte complex micelles (PCMs, core-shell nanoparticles formed by complexation of a polyelectrolyte with a hydrophilic charged-neutral block copolymer) offer a solution to this critical problem. Still, few systematic studies have been conducted on how parameters such as polymer charge density, hydrophobicity, and choice of charged group influence PCM properties, despite evidence that these strongly influence the complexation behavior of polyelectrolyte homopolymers. Using small angle X-ray scattering (SAXS) and electron microscopy we investigate the relationship between the physical properties of oligonucleotide PCMs and chemical properties of the nucleic acids and block copolymers that form them. For instance, differences in charge density and hydrophobicity have been individually suggested to provide increased complex stability, but we find that other factors may disrupt this trend. These observations narrow the design space for optimizing therapeutic PCMs and provide new insights into the rich polymer physics of polyelectrolyte self-assembly.