{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:07:13Z","timestamp":1785424033710,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,13]]},"group-title":"Bioengineering","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["2004947"],"award-info":[{"award-number":["2004947"]}],"id":[{"id":"https:\/\/ror.org\/05sk14837","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["1R01GM121612"],"award-info":[{"award-number":["1R01GM121612"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["4R42CA275425"],"award-info":[{"award-number":["4R42CA275425"]}]},{"name":"National Cancer Institute","award":["5R01CA251730"],"award-info":[{"award-number":["5R01CA251730"]}]},{"DOI":"10.13039\/100000090","name":"Department of Defense Congressionally Directed Medical Research Programs","doi-asserted-by":"crossref","award":["CDMRP MD230034"],"award-info":[{"award-number":["CDMRP MD230034"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Oligonucleotide therapeutics hold transformative potential, yet their clinical translation is hindered by delivery barriers, including rapid renal\/hepatic clearance and poor organ specificity. Bottlebrush polymers 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 \u201cdigital\u201d bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physiochemical 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-\u03b1 achieves potent knockdown and drives full functional recovery. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications.<\/jats:p>","DOI":"10.64898\/2026.05.09.723525","type":"posted-content","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:00:20Z","timestamp":1778691620000},"source":"Crossref","is-referenced-by-count":0,"title":["Sequence-Defined Digital Bottlebrush Polymers for Programmable Oligonucleotide Delivery"],"prefix":"10.64898","author":[{"given":"Jiachen","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guobin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiru","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaobo","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Northeastern University, Boston, MA, USA"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Cavazos","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-6702","authenticated-orcid":false,"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, 02115, USA"},{"name":"Department of Bioengineering, Northeastern University, Boston, Massachusetts, 02115, USA"},{"name":"Department of Chemical Engineering, Northeastern University, Boston, Massachusetts, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051605550514000_2026.05.09.723525v1.1","doi-asserted-by":"crossref","unstructured":"Lim, K.H. et al. 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