Structure-Property Relationships for Oligonucleotide Polyelectrolyte Complex Micelles

When a charged-neutral hydrophilic block copolymer is mixed with an oppositely-charged polyelectrolyte, micro-phase separation occurs, producing core-shell nanoparticles referred to as polyelectrolyte complex micelles by analogy to hydrophobically-driven micellization. PCMs have been proposed as a solution to the urgent problem of therapeutic delivery of (anionic) oligonucleotides into cells, as the dense polyelectrolyte core and neutral corona can shield the oligonucleotides from degradation and improve biodistribution. Several promising results have been reported, but until recently no structure-function relations existed to guide design of PCMs, and little data existed on the effect of chemical modifications to either polyelectrolyte. By combining small-angle X-ray scattering, multi-angle light scattering, and cryo-electron microscopy, we have characterized the morphology and internal structure of PCMs formed by oligonucleotides of varying size, structure, and chemical composition with poly(lysine)-poly(ethylene glycol) block copolymers. I will present results that illustrate the connections between molecular features and PCM morphology, as well as rules for producing oligonucleotide PCMs of desired size and shape with exceptionally low polydispersity.