Merging nucleic acids with synthetic polymers via ring-opening metathesis polymerization

Abstract

Nucleic acids, an important class of macromolecules, can be found in cells and viruses. In addition to storing the genetic information for living organisms, many forms of them have great potential in therapeutic applications, such as antisense DNA, small interfering RNA, and aptamers. Integrating nucleic acids with other classes of materials is often required to overcome the intrinsic issues (e.g., poor enzymatic stability and low cellular uptake) and to introduce additional functionalities. Although various strategies have been developed, the synthesis of nucleic acids containing polymers is always challenging due to, for example, poor organic solubility and incompatibility with certain functional groups of the nucleic acids. Among them, three-dimensional bottlebrush-type polymers, which are traditionally more difficult to synthesize, with a high-density arrangement of nucleic acid side chains, exhibit exceptional properties, such as enhanced enzymatic stability and cellular endocytosis abilities. Therefore, we developed a facile synthetic strategy to prepare bottlebrush-type poly(oligonucleotide)s using charge-neutral, organics-soluble and temporarily protected oligonucleotide macromonomers. Oligonucleotide macromonomers can be polymerized in high yields via ring-opening metathesis polymerization (ROMP) to give the bottlebrush precursor, which, upon mild deprotection, yields water-soluble bottlebrush-type poly(oligonucleotide)s. Moreover, molecularly pure, monodisperse DNA strands can be fractionated when carried out at low monomer-to-catalyst ratios. In addition, the preparation of DNA-containing copolymer structures, such as DNA-poly(ethylene glycol) (PEG) diblock graft copolymers and DNA amphiphiles, can be substantially simplified via this strategy. We further explored this synthetic system by introducing a polymerizable norbornene phosphoramidite modifier. This modifier can be incorporated at any position within the DNA strand during the solid-phase oligonucleotide synthesis. The modularized approach makes it possible to add an extra layer of structural complexity to the protected oligonucleotide macromonomers. Via ROMP, not only DNA brush polymers but also two distinct types of architecturally complex poly(oligonucleotide)-co-PEG bottlebrush polymers can be prepared, providing the opportunity to investigate the impact of polymer architecture on biological properties. We anticipate that with expanding access to DNA-polymer conjugates of more complex structures, the discovery of novel properties and applications of these materials will follow shortly.--Author's abstract