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We herein report the construction of semiconducting polymer pro\u2010nanomodulators (SPpMs) with ultrasound (US)\u2010mediated activatable pharmacological actions for deep\u2010tissue sono\u2010immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death\u2010ligand 1 blocker and an indoleamine 2,3\u2010dioxygenase inhibitor) via a singlet oxygen (<jats:sup>1<\/jats:sup>O<jats:sub>2<\/jats:sub>)\u2010cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of <jats:sup>1<\/jats:sup>O<jats:sub>2<\/jats:sub> under US treatment, even in a deep\u2010tissue depth up to 12\u2005cm. The generated <jats:sup>1<\/jats:sup>O<jats:sub>2<\/jats:sub> not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the <jats:sup>1<\/jats:sup>O<jats:sub>2<\/jats:sub>\u2010cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep\u2010tissue sono\u2010immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune\u2010related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep\u2010seated tumors.<\/jats:p>","DOI":"10.1002\/anie.202305200","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T10:34:37Z","timestamp":1684319677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Activatable Semiconducting Polymer Pro\u2010nanomodulators for Deep\u2010Tissue Sono\u2010immunotherapy of Orthotopic Pancreatic Cancer"],"prefix":"10.1002","volume":"62","author":[{"given":"Jingchao","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Biological Science and Medical Engineering Donghua University  Shanghai 201620 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningyue","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for 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