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TGN-020 exhibits only transient inhibitory effects and lacks cell specificity. Stemmed from the solvent-exposed region of TGN-020, here we synthesized TGN-020\/peptide conjugates which can self-assemble upon dephosphorylation. These conjugates selectively formed supramolecular nanofibers on the plasma membrane of ALP+\/AQP4+ glioma cells, which bind to AQP4 in a multivalent manner. The AQP4\u2013nanofiber interaction turned out to be a sustained inhibition and impeded the water exchange. The occlusion of AQP4 enhanced the sensitivity of glioma xenografts to temozolomide treatment in a subcutaneous mouse model. We envision that protein\u2013assembly interactions represent a promising strategy for enabling multivalent binding to proteins of interest, which lead to the sustained regulation of protein function for potential biomedical applications.<\/jats:p>","DOI":"10.1021\/acsnano.6c03807","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:38:10Z","timestamp":1785854290000},"page":"22505-22516","source":"Crossref","is-referenced-by-count":0,"title":["Enzyme-Instructed\nSupramolecular Assemblies Occlude\nExtrinsic Aquaporin-4 via Multivalent Effect for Sensitized\nGlioma Chemotherapy"],"prefix":"10.1021","volume":"20","author":[{"given":"Ruijia","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing University of Chemical Technology , , ,","place":["Beijing, China, 100029"]},{"name":"National Center for Nanoscience and Technology , , ,","place":["Beijing, China, 100190"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinhang","family":"Jia","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine , ,","place":["Hangzhou, China, 310012"]},{"name":"Zhejiang University , , 1369 West Wenyi Road , ,","place":["Hangzhou, China, 311121"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Kunming Medical University , , ,","place":["Kunming, China, 650500"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibin","family":"Ren","sequence":"additional","affiliation":[{"name":"Beijing University of Chemical Technology , , ,","place":["Beijing, China, 100029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanlin","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing University of Chemical Technology , , ,","place":["Beijing, China, 100029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6826-5616","authenticated-orcid":true,"given":"Debin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Medicine Medical Innovation Research Division of the Chinese PLA General Hospital , ,","place":["Beijing, China, 100853"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxin","family":"Yao","sequence":"additional","affiliation":[{"name":"Beijing University of Chemical Technology , , ,","place":["Beijing, China, 100029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine , ,","place":["Hangzhou, China, 310012"]},{"name":"Zhejiang University , , 1369 West Wenyi Road , ,","place":["Hangzhou, China, 311121"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiliang","family":"Bai","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine , ,","place":["Hangzhou, China, 310012"]},{"name":"Zhejiang University , , 1369 West Wenyi Road , ,","place":["Hangzhou, China, 311121"]},{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9714-4219","authenticated-orcid":true,"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing University of Chemical Technology , , ,","place":["Beijing, China, 100029"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"issue":"1","key":"2026081810302975100_cit1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41572-024-00516-y","article-title":"Glioma","volume":"10","author":"Weller","year":"2024","journal-title":"Nat.\nRev. 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