Endogenous stimuli-derived self-assembled DNA tetrahedron (MESH) for precise imaging and activatable mitochondrial interference therapy

Cancer remains a great danger for health and well-being as well as a challenge for the sustainability of Health Systems worldwide. At the same time, tumor theranostics are hampered by limitations in imaging sensitivity, inadequate specificity, side effects and the emergence of therapeutic resistance. Tumor endogenous-activatable theranostic probes have emerged as critical tools for advancing precision diagnostics and targeted treatment of aggressive malignancies. In this study, we developed an endogenous stimuli-derived self-assembled DNA tetrahedron (MESH) nanodevice for simultaneous tumor visualization and activatable mitochondrial interference therapy. The DNA tetrahedron precisely recognized cancer cells via the Mucin-1 (MUC1) aptamer, and tumor-derived microRNA activated a strand displacement cascade amplification reaction to enable specifically and sensitively fluorescence imaging of malignant lesions. Concurrently, the in situ self-assembly process of DNA tetrahedron was initiated to form a DNA network under the stimulation of microRNA in cytoplasm. The self-assembled DNA network could selectively localize to mitochondria, acting as a polyanionic barrier that disrupts mitochondrial function and induces apoptosis. This endogenous tumor microenvironment-regulated morphological transformation between biocompatible DNA tetrahedral and DNA network with suborganelle interference functions might address the side effects and resistance issues of tumor treatment. The MESH provided a novel strategy for cancer imaging and mitochondrial manipulation through endogenous molecular-guided assembly with potential applications in theranostics.