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Here, we establish a multidimensional analytical framework to systematically quantify structure-surface-function relationships in DNs. Representative DNs with distinct structural architectures, including a one-dimensional rod-like six-helix bundle (6HB), a two-dimensional planar three-point star (3PS), and a three-dimensional tetrahedron (TDN), along with their cholesterol- and PEG20k-modified counterparts, were constructed and comparatively analyzed across serum stability, cellular uptake, inflammatory responses, and in vivo performance. Both structure and surface modification significantly influenced DN behavior. Cholesterol modification generally enhanced cellular uptake across BMDM, HEK293T, and HeLa cells to 1.09 to 3.34 times that of the corresponding unmodified DNs, while reducing serum stability by 44\u201370% after 24 h of incubation in 20% FBS. In contrast, PEG20k modification increased serum stability by 27\u201385% and attenuated inflammatory responses. Notably, identical surface modifications produced distinct biological effects across DNs of different structures, supporting a coupled rather than additive interplay between structure and surface chemistry. This work provides a quantitative basis for correlating DN design parameters with biological outcomes and establishes a generalizable analytical framework for matching DN structure and surface chemistry to application-specific biological requirements.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03267","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T02:02:05Z","timestamp":1786672925000},"page":"24400-24410","source":"Crossref","is-referenced-by-count":0,"title":["Multidimensional\nQuantitative Analysis of Biological\nResponses to DNA Nanoassemblies with Defined Structure and Surface\nChemistry"],"prefix":"10.1021","volume":"98","author":[{"given":"Xinwei","family":"Xia","sequence":"first","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201399"]},{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Dai","sequence":"additional","affiliation":[{"name":"Shanghai University , , ,","place":["Shanghai, China, 200444"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenze","family":"Xiao","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201399"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liman","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5058-4815","authenticated-orcid":true,"given":"Hongzhou","family":"Gu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201399"]},{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200030"]},{"name":"Xiangfu Laboratory , ,","place":["Jiashan, China, 314102"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"8","key":"2026083118460652500_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202111980","article-title":"Framework Nucleic Acids in Nuclear\nMedicine Imaging: Shedding Light on Nano-Bio Interactions","volume":"61","author":"Wang","year":"2022","journal-title":"Angew. Chem., Int. Ed."},{"issue":"7","key":"2026083118460652500_cit2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202311309","article-title":"An Intelligent DNA\nNanoreactor for Easy-to-Read In Vivo Tumor Imaging and Precise Therapy","volume":"63","author":"Mao","year":"2024","journal-title":"Angew. Chem., Int. Ed."},{"issue":"9","key":"2026083118460652500_cit3","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1038\/s42256-023-00707-4","article-title":"A Temporally\nResolved\nDNA Framework State Machine in Living Cells","volume":"5","author":"Zhao","year":"2023","journal-title":"Nat. Mach. Intell."},{"issue":"5","key":"2026083118460652500_cit4","doi-asserted-by":"publisher","first-page":"3620","DOI":"10.1021\/acs.analchem.9b04493","article-title":"Programmable pH-Responsive\nDNA Nanosensors for Imaging Exocytosis and Retrieval of Synaptic Vesicles","volume":"92","author":"Liu","year":"2020","journal-title":"Anal. 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