Authors
Junya Song, Yan Liu, Shifeng Zhao, Cheng Zhu, Hongchang Guo, Jin Chang, Jun Kang
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77817. Sep 16, 2026. Epub Sep 16, 2026.
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 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.
PMID:
42750211
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.
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