HER2-Targeted AIE Nanotheranostics Overcome SHR-A1811 Resistance via Immunogenic Pyroptosis and Tumor-Associated Macrophage Reprogramming in Breast Cancer.

Antibody-drug conjugates (ADCs) have revolutionized HER2-positive breast cancer treatment, yet resistance to next-generation agents such as SHR-A1811 (trastuzumab rezetecan) remains a major challenge arising from poor intratumoral delivery, enhanced DNA damage repair, and an immunosuppressive tumor microenvironment (TME). Here, we engineered HER2-targeted AIE780-A1811 nanoparticles (NPs) by covalently conjugating the mitochondria-directed NIR photosensitizer AIE780 with SHR-A1811 via EDC/Sulfo-NHS-mediated amide coupling. These core-shell NPs exhibit an optimal size for EPR-mediated tumor accumulation, high photothermal conversion efficiency, and stable NIR fluorescence for real-time imaging. Upon 660 nm irradiation, AIE780-A1811 NPs generate robust ROS and potent photothermal effects, inducing tumor cell death and stimuli-responsive SHR-A1811 release to amplify DNA double-strand breaks. Mechanistically, this combination therapy activates the NLRP3 inflammasome-GSDMD axis, driving immunogenic pyroptosis and the release of damage-associated molecular patterns. Concurrently, it reprograms tumor-associated macrophages from an M2-like to an M1-like phenotype, enhances CD8+ T cell infiltration, and reduces regulatory T cells, thereby remodeling the immunosuppressive TME. AIE780-A1811 NPs demonstrate potent antitumor efficacy across SHR-A1811-resistant cell lines, patient-derived organoids, and mouse xenografts, achieving near-complete 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-positive breast cancer.