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Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH\u2010responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor\u2010specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.<\/jats:p>","DOI":"10.1002\/anie.201913522","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T22:11:28Z","timestamp":1580422288000},"page":"7168-7172","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":137,"title":["A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry"],"prefix":"10.1002","volume":"59","author":[{"given":"Yansong","family":"Dong","sequence":"first","affiliation":[{"name":"Guangzhou First People's Hospital School of Medicine South China University of Technology  Guangzhou 510006 P. R. 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