Effects of therapeutic chemical modifications on polyelectrolyte properties of oligonucleotides

Polyelectrolyte complex micelles (PCMs), core-shell nanoparticles formed by complexation of polyelectrolytes and polyelectrolyte - hydrophilic neutral block copolymers, are an interesting laboratory for studying polyelectrolyte physics. They also provide an attractive solution to the longstanding problem of delivering therapeutic nucleic acids into cells, as nucleic acids are highly charged anions and are efficiently complexed by cationic polyelectrolytes. We recently published a set of structure-property data that provides rules for constructing DNA oligonucleotide PCMs with well-controlled morphology and low polydispersity and have found that they are applicable to several other polyelectrolytes, suggesting the possibility of developing general principles for PCM self-assembly. DNA oligonucleotides are accessible and chemically stable but are not bioactive, motivating investigation of how chemical modifications affect oligonucleotides’ polyelectrolyte properties. Surprisingly, we find that even single atom changes (e.g. DNA to RNA, or phosphate to phosphorothioate) can have large effects on the properties of the resulting PCMs. I will discuss these, and their interpretation, which highlight the need to include chemical information in models of polyelectrolyte complexation.