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Here, we engineered HER2\u2010targeted AIE780\u2010A1811 nanoparticles (NPs) by covalently conjugating the mitochondria\u2010directed NIR photosensitizer AIE780 with SHR\u2010A1811 via EDC\/Sulfo\u2010NHS\u2010mediated amide coupling. These core\u2013shell NPs exhibit an optimal size for EPR\u2010mediated tumor accumulation, high photothermal conversion efficiency, and stable NIR fluorescence for real\u2010time imaging. Upon 660\u00a0nm irradiation, AIE780\u2010A1811 NPs generate robust ROS and potent photothermal effects, inducing tumor cell death and stimuli\u2010responsive SHR\u2010A1811 release to amplify DNA double\u2010strand breaks. Mechanistically, this combination therapy activates the NLRP3 inflammasome\u2013GSDMD axis, driving immunogenic pyroptosis and the release of damage\u2010associated molecular patterns. Concurrently, it reprograms tumor\u2010associated macrophages from an M2\u2010like to an M1\u2010like phenotype, enhances CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration, and reduces regulatory T cells, thereby remodeling the immunosuppressive TME. AIE780\u2010A1811 NPs demonstrate potent antitumor efficacy across SHR\u2010A1811\u2010resistant cell lines, patient\u2010derived organoids, and mouse xenografts, achieving near\u2010complete tumor regression with negligible systemic toxicity. This multimodal strategy integrating targeted chemotherapy, photothermal therapy, and immunomodulation offers a promising translational approach to overcome ADC resistance in refractory HER2\u2010positive breast cancer.\n                  <\/jats:p>","DOI":"10.1002\/smll.75840","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:41:19Z","timestamp":1790174479000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HER2\u2010Targeted AIE Nanotheranostics Overcome SHR\u2010A1811 Resistance via Immunogenic Pyroptosis and Tumor\u2010Associated Macrophage Reprogramming in Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1939-8884","authenticated-orcid":false,"given":"Xiaohong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery Southwest Hospital Army Medical University  Chongqing China"},{"name":"Key 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