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Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody\u2010molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity\u2010enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate\u2010L\u2010tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (Z<jats:sub>HER2:342<\/jats:sub>\u2010Cys) to produce Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010Cys. Subsequently, Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010CR8, which can self\u2010assemble into affibody\u2013drug conjugate nanoagent (Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010CR8 ADCN) in PBS. When Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010CR8 ADCN specific binds to human epidermal growth factor receptor 2 (HER2) on cancer cells, the FSY36 of Z<jats:sub>HER2:342<\/jats:sub> approaches to the His490 of HER2 and ultimately reacts with each other to form a covalent bond via SuFEx reaction. Such a covalent binding mode endows Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010CR8 ADCN with permanent binding ability to effectively increase the concentration of drugs in tumor. Eventually, the covalent Z<jats:sub>HER2:342<\/jats:sub>\u201036<jats:sub>FSY<\/jats:sub>\u2010CR8 ADCN exhibits an outstanding tumor inhibition ratio of 90.03\u00a0\u00b1\u00a04.29% in HER2\u2010positive ovary tumor models, strikingly higher than that of the noncovalent one (64.25\u00a0\u00b1\u00a07.71%).<\/jats:p>","DOI":"10.1002\/advs.202412273","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T06:45:38Z","timestamp":1737096338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Covalent Affibody\u2010Molecular Glue Drug Conjugate Nanoagent for Proximity\u2010Enabled Reactive Therapeutics"],"prefix":"10.1002","volume":"12","author":[{"given":"Wenhui","family":"Gao","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Jiao Tong University  Shanghai 200240 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