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Developing activatable strategies for molecular glues remains a formidable challenge due to their compact, featureless scaffolds that resist chemical modification. Herein, we report a sonochemically activatable pro\u2010molecular glue strategy for spatiotemporally controlled targeted protein degradation. By identifying the critical aniline group, a structural linchpin for neosubstrate recruitment, as the optimal caging site, we rationally designed a pro\u2010lenalidomide (PL) equipped with a singlet oxygen (\n                    <jats:sup>1<\/jats:sup>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    )\u2010cleavable self\u2010immolative linker. This prodrug is co\u2010assembled with a semiconducting polymer (SP) sonosensitizer to construct an activatable nanoplatform. Upon ultrasound irradiation, the in situ\u2010generated\n                    <jats:sup>1<\/jats:sup>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    functions as a precise chemical switch, triggering the oxidative cleavage of the linker to uncage the molecular glue within the tumor microenvironment. This \u201coff\u2010to\u2010on\u201d capability orchestrates a potent antitumor response by synergizing sonodynamic stress with reinstated IKZF1\/3 degradation. Uniquely, this strategy confines pharmacological activity strictly to the tumor site, thereby eliciting robust therapeutic efficacy while broadening the therapeutic window. This work establishes a generalizable chemical toolkit for designing activatable molecular glues, paving the way for safer precision cancer therapies.\n                  <\/jats:p>","DOI":"10.1002\/anie.7024563","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:02:14Z","timestamp":1788152534000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Sonochemically Activatable Pro\u2010Molecular Glue for Spatiotemporally Controlled Targeted Protein Degradation"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6372-1530","authenticated-orcid":false,"given":"Qianqian","family":"Mu","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of High\u2010Performance Polymer Materials &amp; Technology, State Key Laboratory of Analytical Chemistry for Life Science The Comprehensive Cancer Centre Nanjing Drum Tower Hospital School of Chemistry Nanjing University  Nanjing P. 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