(468a) Exploring the Impact of Molecular Structure on Oligonucleotide Polyelectrolyte Complex Micelles

Nucleic acids are some of the most highly-charged molecules known, and interact strongly with charged molecules in the cell. Condensation of long double-stranded DNA is a classic and widely researched topic, but the polyelectrolyte behavior of short and/or single-stranded nucleic acids is far less studied despite its importance for both biological and engineered systems. Neutral-cationic block polymers condense nucleic acids driving phase separation on the nanoscale, forming polyelectrolyte complex micelles. These nanoparticles sequester and protect nucleic acids from nucleases and immune response. Here, we present an investigation of the impact of physical and chemical properties of each polyelectrolyte on complex assembly using small angle X-ray scattering and electron microscopy. We find the molecular details of the cationic charged group and nucleic acid backbone strongly influence complexation behavior and stability. Notably, DNA, RNA, and common chemically modified nucleic acids exhibit drastically different behavior in polyelectrolyte complexes that should be considered when designing therapeutic delivery systems. These observations narrow the design space for tailored therapeutic micelles and provide new insights into the physics of polyelectrolyte self-assembly.