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To address the bottlenecks, we innovatively design a Ru(II) metallacycle\u2010based sonosensitizer\/sonocatalyst (named\n                    <jats:bold>Ru\u2010A3\u2010TTD<\/jats:bold>\n                    ) to enhance the potency of sonotherapy by employing molecular engineering strategies tailored to BME. Our approach involves augmenting\n                    <jats:bold>Ru\u2010A3\u2010TTD<\/jats:bold>\n                    \u2019s production of ultrasonic\u2010triggered reactive oxygen species (ROS), surpassing the performance of commercial sonosensitizers, through a straightforward but potent \u03c0\u2010expansion approach. Within the BME,\n                    <jats:bold>Ru\u2010A3\u2010TTD<\/jats:bold>\n                    synergistically amplifies sonotherapeutic efficacy via triple\u2010modulated approaches: (i) effective alleviation of hypoxia, leading to increased ROS generation, (ii) disruption of the antioxidant defense system, which shields ROS from glutathione consumption, and (iii) enhanced biofilm penetration, enabling ROS production in deep sites. Notably,\n                    <jats:bold>Ru\u2010A3\u2010TTD<\/jats:bold>\n                    sono\u2010catalytically oxidizes NADPH, a critical coenzyme involved in antioxidant defenses. Consequently,\n                    <jats:bold>Ru\u2010A3\u2010TTD<\/jats:bold>\n                    demonstrates superior biofilm eradication potency against multidrug\u2010resistant\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    compared to conventional clinical antibiotics, both in vitro and in vivo. To our knowledge, this study represents the pioneering instance of a supramolecular sonosensitizer\/sonocatalyst. It provides valuable insights into the structure\u2010activity relationship of sonosensitizers and paves a promising pathway for the treatment of biofilm infections.\n                  <\/jats:p>","DOI":"10.1002\/anie.202319966","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T02:41:30Z","timestamp":1707360090000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["De Novo Designed Ru(II) Metallacycle as a Microenvironment\u2010Adaptive Sonosensitizer and Sonocatalyst for Multidrug\u2010Resistant Biofilms Eradication"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1139-0855","authenticated-orcid":false,"given":"Yuling","family":"Xu","sequence":"first","affiliation":[{"name":"National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry Central China Normal 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