{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:09:15Z","timestamp":1789567755657,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["4R42CA275425"],"award-info":[{"award-number":["4R42CA275425"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["5R01CA251730"],"award-info":[{"award-number":["5R01CA251730"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["MD230034"],"award-info":[{"award-number":["MD230034"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1R01GM121612"],"award-info":[{"award-number":["1R01GM121612"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Science Foundation (NSF)","award":["2503350"],"award-info":[{"award-number":["2503350"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,16]]},"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 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 \u201cdigital\u201d bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physicochemical properties\u2500including lipids, cholesterol, and cationic groups\u2500along a polyphosphodiester backbone. Systematic evaluation of the digital bottlebrush polymer library reveals distinct structure\u2013property 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 significantly reduced arthritis severity and preserved animal body weight. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications.<\/jats:p>","DOI":"10.1021\/jacs.6c09537","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:20:22Z","timestamp":1788459622000},"page":"38845-38855","source":"Crossref","is-referenced-by-count":0,"title":["Sequence-defined Digital\nBottlebrush Polymers for\nProgrammable Oligonucleotide Delivery"],"prefix":"10.1021","volume":"148","author":[{"given":"Jiachen","family":"Lin","sequence":"first","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2886-6503","authenticated-orcid":true,"given":"Yun","family":"Wei","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Xue","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4373-5723","authenticated-orcid":true,"given":"Jiaming","family":"Xu","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guobin","family":"Xu","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiru","family":"Chen","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5257-6775","authenticated-orcid":true,"given":"Shaobo","family":"Yang","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"Dana-Farber Cancer Institute , , , ,","place":["Boston, Massachusetts, United States, 02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe","family":"Cavazos","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Shen","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Wang","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Wang","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-6702","authenticated-orcid":true,"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]},{"name":"Northeastern University , , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"2026091609112819700_cit1","doi-asserted-by":"publisher","first-page":"3501","DOI":"10.1038\/s41467-020-17093-9","article-title":"Antisense oligonucleotide modulation of non-productive alternative\nsplicing upregulates gene expression","volume":"11","author":"Lim","year":"2020","journal-title":"Nat. Commun."},{"issue":"10","key":"2026091609112819700_cit2","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s41573-020-0075-7","article-title":"Advances in oligonucleotide\ndrug\ndelivery","volume":"19","author":"Roberts","year":"2020","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"2","key":"2026091609112819700_cit3","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/path.2993","article-title":"Silencing disease\ngenes in the laboratory and the clinic","volume":"226","author":"Watts","year":"2012","journal-title":"J. Pathol."},{"issue":"22","key":"2026091609112819700_cit4","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202405083","article-title":"Enhancing the Pharmacokinetics of Aptamers: Targeting AXL In Vivo\nUsing a Bottlebrush Polymer-Conjugated Aptamer","volume":"14","author":"Sun","year":"2025","journal-title":"Adv. Healthc Mater."},{"issue":"4","key":"2026091609112819700_cit5","doi-asserted-by":"publisher","first-page":"433","DOI":"10.3390\/biomedicines9040433","article-title":"The Challenges and Strategies of Antisense Oligonucleotide\nDrug Delivery","volume":"9","author":"Gagliardi","year":"2021","journal-title":"Biomedicines"},{"issue":"4","key":"2026091609112819700_cit6","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202013243","article-title":"Delivery of oligonucleotide-based\ntherapeutics:\nchallenges and opportunities","volume":"13","author":"Hammond","year":"2021","journal-title":"EMBO Mol. Med."},{"issue":"3","key":"2026091609112819700_cit7","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/nbt.3765","article-title":"The chemical evolution\nof oligonucleotide therapies\nof clinical utility","volume":"35","author":"Khvorova","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"2026091609112819700_cit8","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1080\/14712598.2017.1273344","article-title":"Antibody\u2013siRNA\nconjugates: drugging the undruggable for anti-leukemic therapy","volume":"17","author":"Tushir-Singh","year":"2017","journal-title":"Expert Opin. Biol. Ther."},{"issue":"11","key":"2026091609112819700_cit9","doi-asserted-by":"publisher","first-page":"4739","DOI":"10.1172\/JCI128205","article-title":"Peptide-conjugated oligonucleotides\nevoke long-lasting\nmyotonic dystrophy correction in patient-derived cells and mice","volume":"129","author":"Klein","year":"2019","journal-title":"J. Clin. Invest."},{"issue":"3","key":"2026091609112819700_cit10","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3390\/pharmaceutics5030498","article-title":"Advances in Lipid Nanoparticles for\nsiRNA Delivery","volume":"5","author":"Tam","year":"2013","journal-title":"Pharmaceutics"},{"issue":"7","key":"2026091609112819700_cit11","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nrd1775","article-title":"Design and development\nof polymers for gene delivery","volume":"4","author":"Pack","year":"2005","journal-title":"Nat. Rev. Drug\nDiscovery"},{"issue":"10","key":"2026091609112819700_cit12","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1038\/s12276-023-01086-x","article-title":"Immunogenicity\nof lipid nanoparticles and its impact on the efficacy of mRNA vaccines\nand therapeutics","volume":"55","author":"Lee","year":"2023","journal-title":"Exp. Mol. Med."},{"issue":"14","key":"2026091609112819700_cit13","doi-asserted-by":"publisher","first-page":"6518","DOI":"10.1093\/nar\/gkw236","article-title":"The delivery\nof therapeutic oligonucleotides","volume":"44","author":"Juliano","year":"2016","journal-title":"Nucleic Acids\nRes."},{"key":"2026091609112819700_cit14","doi-asserted-by":"publisher","first-page":"115073","DOI":"10.1016\/j.addr.2023.115073","article-title":"RNAi therapies: Expanding applications for extrahepatic\ndiseases and overcoming delivery challenges","volume":"201","author":"Won Lee","year":"2023","journal-title":"Adv. Drug Delivery Rev."},{"issue":"8","key":"2026091609112819700_cit15","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1016\/j.ymthe.2020.06.015","article-title":"Delivery of\nOligonucleotides to the Liver with GalNAc: From Research to Registered\nTherapeutic Drug","volume":"28","author":"Debacker","year":"2020","journal-title":"Mol. Ther."},{"issue":"7","key":"2026091609112819700_cit16","doi-asserted-by":"publisher","first-page":"6870","DOI":"10.1021\/acs.jmedchem.4c02528","article-title":"Metabolic Stability\nand Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics\nBeyond The Liver","volume":"68","author":"Anand","year":"2025","journal-title":"J. Med. Chem."},{"issue":"3","key":"2026091609112819700_cit17","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1093\/nar\/gky1239","article-title":"Diverse lipid\nconjugates\nfor functional extra-hepatic siRNA delivery in vivo","volume":"47","author":"Biscans","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2026091609112819700_cit18","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.jconrel.2023.12.035","article-title":"Enabling safer, more\npotent oligonucleotide therapeutics with bottlebrush polymer conjugates","volume":"366","author":"Chen","year":"2024","journal-title":"J. Controlled Release"},{"key":"2026091609112819700_cit19","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202204576","article-title":"A Long-Circulating Vector\nfor Aptamers Based upon Polyphosphodiester-Backboned\nMolecular Brushes","volume":"61","author":"Wang","year":"2022","journal-title":"Angew. Chem., Int. Ed."},{"issue":"29","key":"2026091609112819700_cit20","doi-asserted-by":"publisher","first-page":"9097","DOI":"10.1021\/jacs.6b05787","article-title":"Effective Antisense Gene Regulation\nvia Noncationic, Polyethylene\nGlycol Brushes","volume":"138","author":"Lu","year":"2016","journal-title":"J. Am. Chem. Soc."},{"issue":"50","key":"2026091609112819700_cit21","doi-asserted-by":"publisher","first-page":"34763","DOI":"10.1021\/jacs.4c13285","article-title":"Bottlebrush Polymers\nwith Sequence-Controlled\nBackbones for Enhanced Oligonucleotide Delivery","volume":"146","author":"Wei","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026091609112819700_cit22","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.omtn.2018.04.004","article-title":"Antibody-Antisense\nOligonucleotide Conjugate Downregulates a Key Gene in Glioblastoma\nStem Cells","volume":"11","author":"Arnold","year":"2018","journal-title":"Molecular Therapy Nucleic Acids"},{"issue":"6","key":"2026091609112819700_cit23","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/icb.2013.15","article-title":"Regulation of TNF-\u03b1\nwith a focus on rheumatoid arthritis","volume":"91","author":"Moelants","year":"2013","journal-title":"Immunol.\nCell Biol."},{"issue":"8","key":"2026091609112819700_cit24","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.3390\/ijms19082244","article-title":"Anti-TNF Therapy\nin Crohn\u2019s Disease","volume":"19","author":"Adegbola","year":"2018","journal-title":"Int. J. Mol. Sci."},{"issue":"3","key":"2026091609112819700_cit25","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.4049\/jimmunol.157.3.1261","article-title":"Disparate\nCD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory\nbowel disease. Crohn\u2019s disease LP cells manifest increased\nsecretion of IFN-gamma, whereas ulcerative colitis LP cells manifest\nincreased secretion of IL-5","volume":"157","author":"Fuss","year":"1996","journal-title":"J. Immunol."},{"issue":"5","key":"2026091609112819700_cit26","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/nprot.2007.173","article-title":"Collagen-induced\narthritis","volume":"2","author":"Brand","year":"2007","journal-title":"Nat. Protoc."},{"issue":"3","key":"2026091609112819700_cit27","doi-asserted-by":"publisher","first-page":"939","DOI":"10.3892\/etm.2021.10371","article-title":"Applicability and implementation\nof the collagen-induced arthritis mouse model, including protocols","volume":"22","author":"Luan","year":"2021","journal-title":"Exp. Ther. Med."},{"issue":"3","key":"2026091609112819700_cit28","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1002\/jcsm.12280","article-title":"Collagen-induced arthritis as an animal\nmodel of rheumatoid cachexia","volume":"9","author":"Alabarse","year":"2018","journal-title":"J. Cachexia Sarcopenia\nMuscle"},{"issue":"5","key":"2026091609112819700_cit29","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1002\/anie.201610753","article-title":"Effect of\nPEG Architecture on the Hybridization Thermodynamics and Protein Accessibility\nof PEGylated Oligonucleotides","volume":"56","author":"Jia","year":"2017","journal-title":"Angew. Chem.\nInt. Ed."},{"issue":"29","key":"2026091609112819700_cit30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2113180119","article-title":"Targeting oncogenic KRAS with molecular brush-conjugated antisense\noligonucleotides","volume":"119","author":"Wang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U.\nS. A."},{"key":"2026091609112819700_cit31","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.omtn.2016.12.011","article-title":"Cholesterol-Containing\nNuclease-Resistant siRNA Accumulates in Tumors in a Carrier-free Mode\nand Silences MDR1 Gene","volume":"6","author":"Chernikov","year":"2017","journal-title":"Mol. Ther.--Nucleic\nAcids"},{"issue":"2","key":"2026091609112819700_cit32","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/s001090050200","article-title":"Integrin receptor-targeted\ntransfer peptides for efficient delivery of antisense oligodeoxynucleotides","volume":"76","author":"Bachmann","year":"1998","journal-title":"J. Mol. Med."},{"issue":"4","key":"2026091609112819700_cit33","doi-asserted-by":"publisher","first-page":"2975","DOI":"10.3390\/cimb46040186","article-title":"Precision Dermatology:\nA Review of Molecular Biomarkers and Personalized Therapies","volume":"46","author":"Tan","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"issue":"3","key":"2026091609112819700_cit34","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1172\/JCI125228","article-title":"Selective tissue targeting of synthetic\nnucleic acid drugs","volume":"129","author":"Seth","year":"2019","journal-title":"J. Clin. Invest."},{"issue":"4","key":"2026091609112819700_cit35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0175207","article-title":"The impact of anti-drug antibodies on drug\nconcentrations and clinical outcomes in rheumatoid arthritis patients\ntreated with adalimumab, etanercept, or infliximab: Results from a\nmultinational, real-world clinical practice, non-interventional study","volume":"12","author":"Moots","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"2026091609112819700_cit36","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1124\/jpet.102.040329","article-title":"Antisense oligonucleotide\nblockade\nof tumor necrosis factor-alpha in two murine models of colitis","volume":"304","author":"Myers","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c09537","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/36\/38845\/68248169\/jacs.6c09537.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/36\/38845\/68248169\/jacs.6c09537.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:34:39Z","timestamp":1789565679000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/36\/38845\/5409520\/Sequence-defined-Digital-Bottlebrush-Polymers-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":36,"journal-issue":{"issue":"36","published-online":{"date-parts":[[2026,9,2]]},"published-print":{"date-parts":[[2026,9,16]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c09537","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]}}}