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Peer-reviewedCC BY-NC-NDJournal of the American Chemical Society

Sequence-defined Digital Bottlebrush Polymers for Programmable Oligonucleotide Delivery.

  • Jiachen Lin1
  • Tingyu Sun1
  • Yun Wei1
  • Chenyang Xue1
  • Jiaming Xu2
  • Guobin Xu1
  • Peiru Chen1
  • Yuyan Wang1
  • Shaobo Yang3,4
  • Chloe Cavazos1
  • Caroline Shen1
  • Allison Wang1
2 more authors
  • Alex Wang1
  • Ke Zhang1,3,2
4 affiliations
  1. 1Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts02115, United States.
  2. 2Department of Chemical Engineering, Northeastern University, Boston, Massachusetts02115, United States.
  3. 3Department of Bioengineering, Northeastern University, Boston, Massachusetts02115, United States.
  4. 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts02215, United States.
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Abstract

Oligonucleotide therapeutics hold transformative potential, yet their clinical translation is hindered by delivery barriers, including rapid renal/hepatic clearance and poor organ specificity. Bottlebrush polymer conjugates have emerged as a promising vector to address these limitations, but conventional architectures with uniform backbones can only achieve an unmodifiable, rigid biodistribution profile. Here, we report a library of sequence-defined "digital" bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physicochemical properties─including lipids, cholesterol, and cationic groups─along a polyphosphodiester backbone. Systematic evaluation of the digital bottlebrush polymer library reveals distinct structure-property relationships and enables organ-biased systemic delivery to several traditionally difficult-to-reach tissues, including muscle and skin. In a mouse model of rheumatoid arthritis, a single dose of a spleen-homing polymer-conjugated antisense oligonucleotide targeting TNF-α significantly reduced arthritis severity and preserved animal body weight. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications.

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Cite

BibTeXRIS
BibTeX
@article{lin2026sequencedefined,
  title = {{Sequence-defined Digital Bottlebrush Polymers for Programmable Oligonucleotide Delivery.}},
  author = {Jiachen Lin and Tingyu Sun and Yun Wei and Chenyang Xue and Jiaming Xu and Guobin Xu and Peiru Chen and Yuyan Wang and Shaobo Yang and Chloe Cavazos and Caroline Shen and Allison Wang and Alex Wang and Ke Zhang},
  journal = {Journal of the American Chemical Society},
  year = {2026},
  month = sep,
  doi = {10.1021/jacs.6c09537},
  url = {https://europepmc.org/article/MED/42915543},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Sequence-defined Digital Bottlebrush Polymers for Programmable Oligonucleotide Delivery.
AU  - Jiachen Lin
AU  - Tingyu Sun
AU  - Yun Wei
AU  - Chenyang Xue
AU  - Jiaming Xu
AU  - Guobin Xu
AU  - Peiru Chen
AU  - Yuyan Wang
AU  - Shaobo Yang
AU  - Chloe Cavazos
AU  - Caroline Shen
AU  - Allison Wang
AU  - Alex Wang
AU  - Ke Zhang
PY  - 2026
DA  - 2026/09/01
JO  - Journal of the American Chemical Society
DO  - 10.1021/jacs.6c09537
UR  - https://europepmc.org/article/MED/42915543
AB  - Oligonucleotide therapeutics hold transformative potential, yet their clinical translation is hindered by delivery barriers, including rapid renal/hepatic clearance and poor organ specificity. Bottlebrush polymer conjugates have emerged as a promising vector to address these limitations, but conventional architectures with uniform backbones can only achieve an unmodifiable, rigid biodistribution profile. Here, we report a library of sequence-defined "digital" bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physicochemical properties─including lipids, cholesterol, and cationic groups─along a polyphosphodiester backbone. Systematic evaluation of the digital bottlebrush polymer library reveals distinct structure-property relationships and enables organ-biased systemic delivery to several traditionally difficult-to-reach tissues, including muscle and skin. In a mouse model of rheumatoid arthritis, a single dose of a spleen-homing polymer-conjugated antisense oligonucleotide targeting TNF-α significantly reduced arthritis severity and preserved animal body weight. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications.
SN  - 0002-7863
SN  - 1520-5126
ER  -