Bottlebrush Polymers\nwith Sequence-Controlled Backbones\nfor Enhanced Oligonucleotide Delivery

The clinical translation\nof oligonucleotide-based therapeutics\ncontinues to encounter challenges in delivery. In this study, we introduce\na novel class of delivery vehicles for oligonucleotides that are based\non poly(ethylene glycol) (PEG) bottlebrush polymers with sequence-defined\nbackbones. Using solid-phase synthesis and bespoke phosphoramidites,\nthe oligonucleotide and the polymer backbone can be assembled on the\nsolid support. The synthesis allows chemical modifiers such as carbon\n18 (C<sub>18</sub>) units to be incorporated into the backbone in\nspecific patterns to modulate the cell–material interactions.\nSubsequently, PEG side chains were grafted onto the polymer segment\nof the resulting polymer–oligonucleotide conjugate, yielding\nbottlebrush polymers. We report an optimal pattern of the C<sub>18</sub> modifier that leads to improved cellular uptake, plasma pharmacokinetics,\nbiodistribution, and antisense activity <i>in vivo</i>.\nOur results provide valuable insights into the structure–property\nrelationship of polymer–oligonucleotide conjugates and suggest\nthe possibility of tuning the polymer backbone to meet the specific\ndelivery requirements of various diseases.