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, which are based on polyeth-ylene glycol (PEG) bottlebrush polymers with sequence-defined backbones. Using solid-phase synthesis and bespoke phosphoramidites, the oligonucleotide and the polymer backbone can both 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-materials 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 pacDNA structure-property relationship and suggest a possibility of tuning the polymer backbone to meet the specific delivery requirements of various diseases.