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Here, we report neutral borate buffer can trigger diazo compounds into carbene for protein labeling without the need for acid, metal, or light. We show that such boron\u2010diazo\u2010mediated covalent modification rapidly occurs within seconds under physiological conditions and preferentially targets carboxylate\u2010containing amino acid residues. Towards applications of such boron\u2010diazo protein chemistry, we exemplify the design of an affinity\u2010based covalent inhibitor for dihydrofolate reductase by installing diazo on the non\u2010covalent trimethoprim drug. When extended to stressed cells, we also capture cellular aggresomes using a diazo\u2010Thioflavin T probe that selectively labels aggregated proteins. Finally, in Alzheimer's disease brain tissue, we employ this boron\u2010diazo chemistry to label, enrich, and profile amyloid plaques, identifying proteins related to pathological deposition. Together, the boron\u2010diazo chemistry reported herein provides a rapid and facile protein modification strategy under mild conditions.<\/jats:p>","DOI":"10.1002\/anie.1990347","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:16:18Z","timestamp":1785428178000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutral Borate Buffer Activates Diazo for Rapid Protein Labeling"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0240-9825","authenticated-orcid":false,"given":"Di","family":"Shen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Chromatographic R. &amp; A. 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