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Here, we report a hydrolytically degradable PEG bottlebrush polymer (D-BrushPEG) created by incorporating 7-oxa-2,3-diazanorbornene (ODAN) units into the backbone. D-BrushPEG retains prolonged circulation (elimination half-life \u224824.7 h, compared with \u22480.78 h for a small-molecule dye) while undergoing controlled hydrolysis that greatly improves systemic and tissue clearance. More than 99% of the circulating signal is removed within 13 days, accompanied by a near-complete loss of liver and skin fluorescence. In contrast, a nondegradable BrushPEG analog exhibits slower plasma elimination (\u223c5% remaining at day 13) and persistent accumulation in the liver and skin for over one month. When conjugated with gemcitabine (GEM) through a reduction-responsive self-immolative linker, D-BrushPEG demonstrated comparable antitumor efficacy to the nondegradable BrushPEG-GEM formulation. Systemic evaluation indicates comparable hepatic and renal safety profiles for both polymers, with only mild renal changes observed, while skin irritation is reduced for D-BrushPEG relative to BrushPEG. These results demonstrate that controlled backbone hydrolysis allows PEG bottlebrush polymers to balance long circulation with efficient clearance, reducing tissue persistence and the risk of side effects.<\/jats:p>","DOI":"10.1021\/polymscitech.6c00029","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T10:43:57Z","timestamp":1780397037000},"page":"693-705","source":"Crossref","is-referenced-by-count":2,"title":["Hydrolytically\nDegradable Polyethylene Glycol Bottlebrush\nPolymers Address the Stability-Clearance Trade-Off for Drug Delivery"],"prefix":"10.1021","volume":"2","author":[{"given":"Yixing","family":"Wen","sequence":"first","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingdi","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Mi","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhi","family":"Shi","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Laboratory Animal Center of Institute of Biophysics, Chinese Academy of Sciences , ,","place":["Beijing, China, 100101"]},{"name":"Aviation General Hospital of Beijing , ,","place":["Beijing, China, 100012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"Chinese PLA General Hospital , , ,","place":["Beijing, China, 100853"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8698-309X","authenticated-orcid":true,"given":"Wei","family":"You","sequence":"additional","affiliation":[{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1069-7265","authenticated-orcid":true,"given":"Xueguang","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Chinese Academy of Sciences , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"issue":"3","key":"2026092209080252200_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN\nestimates of incidence and mortality worldwide for 36 cancers in 185\ncountries","volume":"74","author":"Bray","year":"2024","journal-title":"Cancer J. 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