Sonogenetics Nanomedicine Activates the cGAS‐STING Pathway for Immunotherapy of Triple‐Negative Breast Cancer

ABSTRACT Due to pronounced tumor heterogeneity and the lack of effective therapeutic options, triple‐negative breast cancer (TNBC) remains a formidable clinical challenge for the development of effective medicines. Here, we report a HER3‐targeted sonogenetic mechano‐immunomodulatory nanoplatform (HSMIN‐LNP), achieving integrated synergistic therapy for TNBC. HSMIN‐LNP employs a de novo AI‐designed HER3‐targeting miniprotein (HTIM) and co‐delivers the TRPV4 (mechanosensory) plasmid together with an NFAT‐promoted IL‐15 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)‐triggered local IL‐15 induction through TRPV4‐mediated Ca 2+ /NFAT signaling. Mechanistically, US‐activated TRPV4 further elicited pronounced Ca 2+ overload, reactive oxygen species accumulation, mitochondrial damage, and apoptosis in tumor cells. It simultaneously activated cGAS‐STING‐dependent inflammatory and interferon signaling pathways, thereby contributing to tumor cell death and immune‐associated antitumor responses. In vivo studies further verified that HSMIN‐LNP significantly enhanced dendritic cell maturation, NK cell and CD8 + T cell responses, as well as memory T cell formation. Collectively, this study provides a promising avenue for integrated precision therapy of TNBC.