Expanding the architectural horizon of nucleic-acid-polymer biohybrids by site-controlled incorporation of ATRP initiators in DNA and RNA

Modifying biomacromolecules with synthetic polymers has been a powerful approach to developing multifunctional hybrid biomaterials for nanoscience and biomedical applications. With oligonucleotides, limited coupling and conjugation strategies were replaced with approaches allowing for the initiation of polymer chains directly from a terminus of synthetic DNA sequences. Although these strategies have provided access to diblock (DNA-polymer) bioconjugates, oligonucleotide biohybrids with more complex architectures have remained challenging. In this work, we vastly expand the possibility of creating diverse oligonucleotide-polymer biohybrids by developing serinol-based α-bromoisobutyryl (SBiB) phosphoramidite. This universal reagent allows for multiple site-specific incorporations of an atom-transfer radical polymerization (ATRP) initiator within a synthetic DNA or RNA sequence. Combining this methodology with the recently developed green-light-induced ATRP with dual catalysis has enabled the precise fabrication of well-defined, complex hybrid nucleic acid polymers.