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Theranostic nanoplatforms with integrated diagnostic imaging and multiple therapeutic functions play a vital role in precise diagnosis and efficient treatment for breast cancer, but unfortunately, these nanoplatforms are usually stuck in single-site imaging and single mode of treatment, causing unsatisfactory diagnostic and therapeutic efficiency. Herein, a dual biomarkers-activatable facile hollow mesoporous MnO 2 (H–MnO 2)-based theranostic nanoplatform, DNAzyme@H–MnO 2 -MUC1 aptamer (DHMM), was constructed for the simultaneous multi-site diagnosis and multiple treatment of breast cancer. The DHMM acted as an integrated diagnostic and therapeutic nanoplatform that realizes multi-site fluorescence imaging-guided high-efficient photothermal/chemodynamic/gene synergistic therapy (PTT/CDT/GT) for breast cancer. The H–MnO 2 exhibits high loading capacity for Cy5-MUC1 aptamer (3.05 pmoL μg−1) and FAM-DNAzyme (3.37 pmoL μg−1), and excellent quenching for the probes. In the presence of MUC1 on the cell membrane and GSH in the cytoplasm, Cy5-MUC1 aptamer and FAM-DNAzyme was activated triggering dual-channel fluorescence imaging at different sites. Moreover, the self-supplied Mn2+ was further supplied as DNAzyme cofactors to catalytic cleavage intracellular EGR-1 mRNA for high-efficient GT and stimulated the Fenton-like reaction for CDT. The H–MnO 2 also showcases a favorable photothermal performance with a photothermal conversion efficiency of 44.16%, which ultimately contributes to multi-site fluorescence imaging-guided synergistic treatment with an apoptosis rate of 71.82%. This dual biomarker-activatable multiple therapeutic nanoplatform was realized multi-site fluorescence imaging-guided PTT/CDT/GT combination therapy for breast cancer with higher specificity and efficiency, which provides a promising theranostic nanoplatform for the precision and efficiency of breast cancer treatment. [Display omitted] • DHMM realized multi-site imaging and highly efficient PTT/CDT/GT synergistic therapy with a final apoptosis rate of 71.82%. • The H–MnO 2 exhibits large loading capacity for FAM-DNAzyme (3.37 pmoL μg−1) and Cy5-MUC1 aptamer (3.05 pmoL μg−1). • The H–MnO 2 showcases excellent photothermal properties with a photothermal conversion efficiency of 44.16%. [ABSTRACT FROM AUTHOR]