Magneto-photo-acoustic Nanotheranostics Orchestrate Ferroptosis–Immune Cross Talk for Spatiotemporally Amplified Triple-Negative Breast Cancer Therapy

Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive behavior, immunosuppressive tumor microenvironment, and lack of effective targeted therapies. To address these limitations, we developed a magneto-photo-acoustic responsive nanoplatform (MnFe ₂ O ₄ –erastin–perfluoropentane nanoparticles [MEPNPs]). This nanoplatform features 3-tiered therapeutic innovations: (a) Multimodal imaging-guided precision therapy: The superparamagnetic property of MnFe ₂ O ₄ enabled magnetic resonance and photoacoustic imaging, allowing real-time visualization of tumor margins. (b) Spatiotemporally controlled ferroptosis activation: Magnetic targeting enhanced the tumor accumulation of MEPNPs, while near-infrared irradiation triggered perfluoropentane vaporization for burst erastin release. This dual strategy combinationally suppressed glutathione peroxidase 4 and amplified the accumulation of lipid peroxides, achieving the amplification of ferroptosis. (c) Immunogenic tumor microenvironment reprogramming: MEPNP-induced immunogenic cell death promoted dendritic cell maturation and CD8 ⁺ T-cell infiltration, effectively converting immunologically “cold” TNBC tumors into “hot” phenotypes. In TNBC models, MEPNP treatment elicited remarkable therapeutic outcomes: primary tumor suppression, reduction in lung metastasis, and an extended median survival period exceeding 45 d. The transcriptome sequencing results showed that there were 6,198 differentially expressed genes in the treatment group. These included the up-regulation of ferroptosis drivers such as SLC39A14, as well as the down-regulation of antioxidant regulators such as SLC7A11 and SLC3A2. Additionally, Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed that the “ferroptosis” and “T-cell differentiation” pathways were specifically activated. This work establishes a novel “theranostic–immunomodulatory” paradigm that integrates magnetic targeting, ferroptosis potentiation, and immunogenic-cell-death-mediated immune memory. By orchestrating physical energy conversion, MEPNPs provide a spatially focused and immunologically amplified strategy to overcome TNBC therapeutic resistance.