Enzyme-Activatable and Tumor-Targeted Nanosystem for Real-Time Imaging and Synergistic Zn2+-Interference Photothermal Therapy of Breast Cancer Bone Metastasis.

Bone metastasis is a frequent and debilitating complication in advanced breast cancer. Monitoring and treating bone metastasis remains challenging due to the inability of current imaging modalities to capture early molecular changes or provide real-time therapeutic feedback. Here, we report a multifunctional nanosensor (APAZPs) with matrix metalloproteinase-2 (MMP-2)-activatable fluorescence imaging, Zn2+ interference, and photothermal therapy capabilities, for the detection of metastatic lesions. To our knowledge, this is the first nanosystem that combines MMP-2-activatable imaging with Zn2+ interference and photothermal therapy for real-time management of breast cancer bone metastasis. The nanosystem was constructed by assembling gold nanotriangles functionalized with an MMP-2-cleavable Cy5 peptide and the tumor-targeting aptamer AS1411, with PDA-coated AA-[Zn(OH)4]2- nanoparticles via NH2-PEG-SH linkers. The fluorescence of Cy5 in the sensor is restored upon MMP-2-mediated cleavage of the peptide. The sensor exhibited high specificity and a low detection limit of 0.107 ng/mL. In the acidic tumor microenvironment, Zn2+ release is triggered, and the PDA shell generates near-infrared (NIR) photothermal heating with a conversion efficiency of 50.93%. These coordinated responses induced apoptosis in vitro, markedly inhibited cell migration and invasion, and achieved deep penetration into three-dimensional tumor spheroids. In vivo experiments showed that APAZPs preferentially accumulated at bone metastatic sites, and upon 808 nm irradiation, they significantly suppressed tumor growth and reduced tumor volume to 45% of the initial size without observable systemic toxicity. This activatable nanosystem is a versatile platform for real-time imaging and synergistic therapy. It is a promising tool for precision intervention in breast cancer bone metastasis.