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This architecture, comprising aptamers and dense brush\u2010shaped oligo(ethylene glycol) (b\u2010OEG) side chains co\u2010grafted onto a peptide backbone, was validated using the thrombin\u2010binding HD1 aptamer. BOB\u2010HD1 exhibited exceptional nuclease resistance, retaining &gt;40% integrity after 2\u00a0h of S1 nuclease exposure (versus complete degradation of free aptamer within 3\u00a0min), while fully preserving G\u2010quadruplex folding, thrombin\u2010binding activity, and antidote\u2010mediated reversibility. In mice, BOB\u2010HD1 achieved a 7.5\u2010fold increase in systemic exposure and sustained anticoagulation for 4\u00a0h, compared to &lt;20\u00a0min for unmodified or linearly PEGylated aptamer. Critically, unlike linear PEG conjugates that induced anti\u2010PEG antibodies and accelerated blood clearance upon repeated dosing, BOB\u2010HD1 induced no detectable anti PEG IgM or IgG responses under the tested conditions and maintained full efficacy upon repeated administration. This dense brush architecture thus addresses key stability, clearance, and PEG associated immunogenicity barriers that have impeded aptamer clinical translation, offering a versatile and controllable platform for durable aptamer therapeutics while minimizing detectable anti PEG antibody responses under the tested conditions.<\/jats:p>","DOI":"10.1002\/adma.73308","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T12:51:38Z","timestamp":1778244698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Brush\u2010on\u2010Brush Architecture Enables Durable and Reversible Aptamer Therapeutics With Minimal PEG Associated Immunogenicity"],"prefix":"10.1002","volume":"38","author":[{"given":"Gengzhi","family":"Ren","sequence":"first","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences  Hangzhou Zhejiang 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