Relating chemical and physical properties controlling oligonucleotide polyelectrolyte complex phase separation*

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 problem of biophysics, 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. Homopolycations and neutral-cationic block copolymers condense nucleic acids driving macro- or nanoscale phase separation, respectively. Here, we present an investigation of the impact of physical and chemical properties of each polyelectrolyte on complex and micelle assembly. We find molecular details including hybridization, charge density, and chemical structure strongly influence complexation behavior and stability. These observations narrow the design space for optimizing therapeutic micelles and provide new insights into the physics of polyelectrolyte self-assembly.