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Here, we report a HER3\u2010targeted sonogenetic mechano\u2010immunomodulatory nanoplatform (HSMIN\u2010LNP), achieving integrated synergistic therapy for TNBC. HSMIN\u2010LNP employs a de novo AI\u2010designed HER3\u2010targeting miniprotein (HTIM) and co\u2010delivers the TRPV4 (mechanosensory) plasmid together with an NFAT\u2010promoted IL\u201015 gene. The results demonstrated that HTIM directly bound and suppressed HER3 signaling, inhibiting the downstream PI3K\/AKT\/mTOR pathway. This process markedly impaired tumor cell migratory capacity. The NPs also exhibited a uniform and stable nanostructure with high plasmid encapsulation efficiency and enabled ultrasound (US)\u2010triggered local IL\u201015 induction through TRPV4\u2010mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/NFAT signaling. Mechanistically, US\u2010activated TRPV4 further elicited pronounced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload, reactive oxygen species accumulation, mitochondrial damage, and apoptosis in tumor cells. It simultaneously activated cGAS\u2010STING\u2010dependent inflammatory and interferon signaling pathways, thereby contributing to tumor cell death and immune\u2010associated antitumor responses. In vivo studies further verified that HSMIN\u2010LNP significantly enhanced dendritic cell maturation, NK cell and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses, as well as memory T cell formation. Collectively, this study provides a promising avenue for integrated precision therapy of TNBC.\n                  <\/jats:p>","DOI":"10.1002\/advs.77817","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:55:16Z","timestamp":1789620916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sonogenetics Nanomedicine Activates the cGAS\u2010STING Pathway for Immunotherapy of Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1483-5094","authenticated-orcid":false,"given":"Junya","family":"Song","sequence":"first","affiliation":[{"name":"School of Life Sciences Faculty of Medicine Tianjin University  Tianjin 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Surgery Beijing Anzhen Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-8526","authenticated-orcid":false,"given":"Jin","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Life Sciences Faculty of Medicine Tianjin University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-4341","authenticated-orcid":false,"given":"Jun","family":"Kang","sequence":"additional","affiliation":[{"name":"School of Life Sciences Faculty of Medicine Tianjin University  Tianjin 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