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To enable controlled delivery, many CO\u2010releasing molecules (CORMs) have been developed. However, their clinical translation has been limited due to concerns about stability, potential toxicity, and insufficient targeting ability. In this study, we report the synthesis and characterization of an enzyme\u2010triggered CO\u2010releasing molecule (\n                    <jats:bold>ET\u2010CORM<\/jats:bold>\n                    ) that can be site\u2010specifically conjugated to antibodies. This novel\n                    <jats:bold>ET\u2010CORM<\/jats:bold>\n                    is built on a biocompatible iron core, and releases CO upon cleavage by the cancer\u2010associated protease cathepsin B (CatB). The incorporation of a bioorthogonal handle into\n                    <jats:bold>ET\u2010CORM<\/jats:bold>\n                    enabled its efficient and site\u2010specific conjugation to the clinically used antibody trastuzumab via the interchain disulfide bonds. The resulting ET\u2010CORM\u2013antibody conjugate (\n                    <jats:bold>ET\u2010CORM\u2010Ab<\/jats:bold>\n                    ) exhibited an average drug\u2010to\u2010antibody ratio (DAR) of 6.8, corresponding to approximately 20 CO molecules per conjugate. This construct allowed for selective intracellular CO delivery to HER2\u2010overexpressing and CatB\u2010expressing cells in vitro. This study represents a metal\u2010based CORM\u2013antibody conjugate activated by a tumor\u2010associated enzymatic trigger, opening new avenues for investigating CO\u2010mediated effects and advancing CO\u2010based cancer therapies to the clinics.\n                  <\/jats:p>","DOI":"10.1002\/anie.202513808","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T08:53:55Z","timestamp":1762505635000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Cathepsin B\u2010Triggered CO\u2010Releasing Molecule with a Non\u2010Toxic Metal Core for Targeted Tumor Delivery"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1192-074X","authenticated-orcid":false,"given":"Inga","family":"\u010cernauskien\u0117","sequence":"first","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Lensfield Road Cambridge CB2 1EW UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7253-6934","authenticated-orcid":false,"given":"Eduardo","family":"Izquierdo\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Chimie ParisTech PSL University CNRS Institute of Chemistry for Life and Health Sciences Laboratory for Inorganic Chemical Biology  Paris F\u201075005 France"},{"name":"Departament de Qu\u00edmica Inorg\u00e0nica i Org\u00e0nica Secci\u00f3 de Qu\u00edmica Org\u00e0nica Universitat de Barcelona (UB) Institut de Biomedicina de la Universitat de Barcelona (IBUB)  Mart\u00ed i Franqu\u00e8s 1\u201311 Barcelona E\u201008028 Spain"}]},{"given":"Sarah","family":"Keller","sequence":"additional","affiliation":[{"name":"Chimie ParisTech PSL University CNRS Institute of Chemistry for Life and Health Sciences Laboratory for Inorganic Chemical Biology  Paris F\u201075005 France"}]},{"given":"Harley","family":"Betts","sequence":"additional","affiliation":[{"name":"Chimie ParisTech PSL University CNRS Institute of Chemistry for Life and Health Sciences Laboratory for Inorganic Chemical Biology  Paris F\u201075005 France"}]},{"given":"Kevin","family":"Cariou","sequence":"additional","affiliation":[{"name":"Chimie ParisTech PSL University CNRS Institute of Chemistry for Life and Health Sciences Laboratory for Inorganic Chemical Biology  Paris F\u201075005 France"}]},{"given":"Vicente","family":"March\u00e1n","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica Inorg\u00e0nica i Org\u00e0nica Secci\u00f3 de Qu\u00edmica Org\u00e0nica Universitat de Barcelona (UB) Institut de Biomedicina de la Universitat de Barcelona (IBUB)  Mart\u00ed i Franqu\u00e8s 1\u201311 Barcelona E\u201008028 Spain"}]},{"given":"Gilles","family":"Gasser","sequence":"additional","affiliation":[{"name":"Chimie ParisTech PSL University CNRS Institute of Chemistry for Life and Health Sciences Laboratory for Inorganic Chemical Biology  Paris F\u201075005 France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6594-8917","authenticated-orcid":false,"given":"Gon\u00e7alo J. 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