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However, this field has long relied on the strong cavitation effects of low\u2010frequency ultrasound, which are incompatible with clinically high\u2010frequency ultrasound (&gt;\u00a01\u00a0MHz), hindering its biomedical applications. Herein, we report a nanogel network topology\u2010programmed mechanochemical strategy, enabling iterative activation of mechanophores under high\u2010frequency (up to 2.4\u00a0MHz) and low\u2010intensity (down to 2\u00a0W\/cm\n                    <jats:sup>2<\/jats:sup>\n                    ) ultrasound. By introducing network topology as a design parameter, we established the relationship between nanogel topology, ultrasound frequency, and mechanochemical activity, revealing that distinct network topologies selectively accumulate mechanical forces under different ultrasound frequencies. Meanwhile, the thermal effect of high\u2010frequency ultrasound lowers the activation barrier of mechanophores, further promoting their efficient activation. Remarkably, under high\u2010frequency ultrasound, nanogels achieve an activation rate of 12.6%\/min, placing it among the most efficient activation systems reported to date. Importantly, combining nanogels with clinical low\u2010intensity focused ultrasound, we developed a new ultrasound\u2010mediated therapeutic paradigm\u2014synergistic sonothermal and mechanochemical therapy, achieving complete elimination of advanced tumors with a single short treatment. This work establishes network topology engineering as a general strategy for programming mechanochemistry, and opens new opportunities for the in vivo biomedical applications of polymer mechanochemistry.\n                  <\/jats:p>","DOI":"10.1002\/anie.4591365","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T12:54:36Z","timestamp":1779713676000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tailored Nanogel Network Topology Enables Clinical Ultrasound\u2010Induced Mechanochemical Activation for In Vivo Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Helin","family":"Li","sequence":"first","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals Zhejiang University of Technology  Hangzhou China"},{"name":"DWI\u2010Leibniz\u2010Institute for Interactive Materials  Aachen 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Aachen Germany"},{"name":"Aachen Maastricht Institute for Biobased Materials Maastricht University  Geleen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7837-7874","authenticated-orcid":false,"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital School of Medicine Zhejiang University  Hangzhou China"},{"name":"DWI\u2010Leibniz\u2010Institute for Interactive Materials  Aachen Germany"},{"name":"Institute for Technical and Macromolecular Chemistry RWTH Aachen University  Aachen 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