Bottlebrush Polymers with Sequence-Controlled Backbones for Enhanced Oligonucleotide Delivery

The clinical translation of oligonucleotide-based therapeutics continues to encounter challenges in delivery. In this study, we introduce a novel class of delivery vehicles for oligonucleotides that are based on poly(ethylene glycol) (PEG) bottlebrush polymers with sequence-defined backbones. Using solid-phase synthesis and bespoke phosphoramidites, the oligonucleotide and the polymer backbone can be assembled on the solid support. The synthesis allows chemical modifiers such as carbon 18 (C₁₈) units to be incorporated into the backbone in specific patterns to modulate the cell-material interactions. Subsequently, PEG side chains were grafted onto the polymer segment of the resulting polymer-oligonucleotide conjugate, yielding bottlebrush polymers. We report an optimal pattern of the C₁₈ modifier that leads to improved cellular uptake, plasma pharmacokinetics, biodistribution, and antisense activity in vivo. Our results provide valuable insights into the structure-property relationship of polymer-oligonucleotide conjugates and suggest the possibility of tuning the polymer backbone to meet the specific delivery requirements of various diseases.