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

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 Ca2+/NFAT signaling. Mechanistically, US-activated TRPV4 further elicited pronounced Ca2+ 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.