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Herein, we report a self\u2010amplifying US\u2010responsive nanoplatform (PMB@R848) for synergistic sonodynamic immunotherapy. The nanotherapeutic was constructed by conjugating the sonosensitizer methylene blue (MB) to polylysine through US\u2010labile urea\u2010based linkages, providing a stable framework for efficient complexation of immunostimulant R848. Under physiological conditions, PMB@R848 exhibited excellent colloidal stability and biocompatibility. Upon US irradiation, the generated reactive oxygen species (ROS) initiated selective cleavage of urea bonds, exposing protonatable amino groups that enhanced intraparticle electrostatic repulsion under mildly acidic tumor microenvironment. This cascade process further accelerated nanoparticle destabilization and established a self\u2010amplified release behavior, enabling synchronized liberation of both MB and R848. The released MB markedly enhanced ROS generation, inducing robust immunogenic cell death and tumor antigen release, while R848 further amplified dendritic cell maturation and systemic antitumor immunity. Benefiting from the synergistic integration of self\u2010amplified SDT and immune activation, PMB@R848 achieved potent inhibition of primary tumors, effectively suppressed recurrence, and established durable immune memory in multiple murine tumor models. This work presents a self\u2010amplifying, US\u2010activatable nanoplatform for precision sonodynamic immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.75117","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:30:54Z","timestamp":1790145054000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Self\u2010Amplifying Ultrasound\u2010Activated Polymeric Prodrug Nanoplatform for Synergistic Sonodynamic Immunotherapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-3770","authenticated-orcid":false,"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Polymer Science and Technology Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun China"},{"name":"Jilin Biomedical Polymers Engineering Laboratory  Changchun 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