Abstract

HER2-positive breast cancer is characterized by aggressive proliferation, high metastatic potential, and immune evasion, yet current HER2-targeted therapies are hindered by resistance and immunosuppressive microenvironments. Here, we report a multifunctional nanoplatform (TanDNA@MnO 2 ) constructed by biomineralizing manganese dioxide with a tandem DNA (TanDNA) that integrates a HER2-targeting DNAzyme for gene silencing and a dsDNA motif for cGAS–STING activation. TanDNA@MnO 2 exhibited favorable colloidal stability, tumor accumulation, and pH/GSH-responsive Mn 2+ release. Mn 2+ served both as a cofactor to enhance DNAzyme catalytic activity and as an immune agonist to stimulate cGAS–STING signaling. Mechanistic studies revealed dual functionality: HER2 silencing directly inhibited oncogenic proliferation and relieved HER2-mediated suppression of cGAS–STING, while dsDNA and Mn 2+ synergistically amplified STING–TBK1–IRF3 activation. Consequently, TanDNA@MnO 2 remodeled the tumor immune microenvironment by promoting M1 macrophage polarization, dendritic cell maturation, and CD8 + T cell infiltration, accompanied by increased production of anti-tumor cytokines and chemokines. In vivo, TanDNA@MnO 2 achieved potent tumor growth inhibition with negligible systemic toxicity, underscoring its promise as a generalizable nucleic acid–metal oxide nanoplatform that combines gene silencing with immunotherapy to overcome resistance and immune evasion in HER2-positive breast cancer.