Molecular Drivers of Oligonucleotide Polyelectrolyte Complex Assembly, Stability, and Dynamics

Polyelectrolyte complexes (PECs) are polymer-rich phases formed through electrostatic and entropic interactions between oppositely charged polymers. Polyelectrolyte complex micelles (PCMs) form when a neutral block is added, providing a compelling platform to protect and stabilize nucleic acids (NAs) in core-shell nanoparticles. PEC and PCM behavior are highly sensitive to molecular and environmental factors, especially with nucleic acids, due to their complex chemical and physical nature. Here, we establish relationships governing their morphology, assembly, and dynamic behavior. This includes how NA structure and sequence, polycation chemistry and size, and mixing methods govern assembly and morphology. We also examine how environmental factors, such as ionic atmosphere or biological fluids, directly affect phase separation, micelle structure, and stability. Finally, we investigate the impact of these factors on PCM dynamic behavior, measuring chain exchange kinetics and morphological transitions. We use a combination of scattering, microscopy, and molecular dynamic simulation methods to provide key insights into the molecular determinants of PEC and PCM assembly and behavior, enabling the rational design of robust dynamic condensates and nanocarriers.