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To address this, we propose spatial conformation engineering as an additional design dimension to decouple these opposing processes. Inspired by the compact, multilamellar architecture of the myelin sheath, we program poly(ethylene glycol) (PEG) chains into a three-dimensional matrix on a DNA tetrahedral framework. Unlike conventional linear or planar PEGylation, this 3D conformation yields a dense yet compact interfacial topology, enabling effective dynamic steric shielding (reducing protein adsorption by &amp;gt;60%) while maintaining a small hydrodynamic diameter (7.2 nm). This design strategy achieves a two-fold extension of blood circulation half-life while promoting a dominant renal elimination pathway (&amp;gt;90% clearance within 24 h). As a proof-of-concept, we functionalize the platform with a bile acid aptamer to construct a \u201cpatrolling\u201d detoxification system capable of continuous sequestration and removal of blood-borne toxins in a murine hypercholanemia model. Our work establishes spatial conformation as a programmable parameter for regulating nanoparticle biodistribution and clearance, thereby shifting the design paradigm from compositional adjustment to architectural control. This architectural control opens avenues for targeted delivery, imaging, and immunotherapy.<\/jats:p>","DOI":"10.1021\/acsami.6c14185","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:02:14Z","timestamp":1790071334000},"page":"52127-52141","source":"Crossref","is-referenced-by-count":0,"title":["Myelin-Inspired 3D PEGylation of Framework Nucleic Acids Enables Simultaneous Long Circulation and Rapid Renal Clearance"],"prefix":"10.1021","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6481-5776","authenticated-orcid":true,"given":"Qian","family":"Chen","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University School of Medicine , , ,","place":["Shanghai, China, 200127"]},{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-5644","authenticated-orcid":true,"given":"Fei","family":"Ding","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefei","family":"Hu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1741-8992","authenticated-orcid":true,"given":"Qien","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9854-2251","authenticated-orcid":true,"given":"Mingqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2372-6624","authenticated-orcid":true,"given":"Jiang","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai University , , ,","place":["Shanghai, China, 200444"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-919X","authenticated-orcid":true,"given":"Ying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Shanghai University , , ,","place":["Shanghai, China, 200444"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7505-2727","authenticated-orcid":true,"given":"Xiaolei","family":"Zuo","sequence":"additional","affiliation":[{"name":"Renji Hospital, School of Medicine, Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200127"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Mou","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University School of Medicine , , ,","place":["Shanghai, China, 200127"]},{"name":"Shanghai Jiao Tong University School of Medicine , , ,","place":["Shanghai, China, 200125"]},{"name":"Shanghai Jiao Tong University School of Medicine , ,","place":["Shanghai, China, 200025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-7565","authenticated-orcid":true,"given":"Zhilei","family":"Ge","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University School of Medicine , , ,","place":["Shanghai, China, 200127"]},{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]},{"name":"Anhui University of Chinese Medicine , , , ,","place":["Hefei, Anhui, China, 230012"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"2026093001075632500_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.114079","article-title":"To PEGylate or not to PEGylate: Immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives","volume":"180","author":"Shi","year":"2022","journal-title":"Adv. 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