A pH-Responsive and Cofactor-Self-Sufficient DNAzyme@ZIF-8 Probe for Imaging APE1 Activity in Tumor Metastasis and Oxidative Stress

Abstract Human apurinic/apyrimidinic endonuclease 1 (APE1) exhibits aberrant expression and distribution as cells acquire metastatic potential. However, the complex intracellular environment often limits the recognition accuracy of probes based on a single target. Leveraging pathophysiology-associated microenvironmental conditions as endogenous triggers enables the spatial control of molecular imaging signals, thereby enhancing the differentiation between cancerous and non-cancerous cells. Herein, we developed a pH-responsive, cofactor-self-sufficient probe for APE1 activity imaging based on the acid-responsiveness of zeolitic imidazolate framework-8 (ZIF-8) and Zn2+-dependent deoxyribozyme (DNAzyme) signal amplification. ZIF-8 not only effectively delivers DNA probes into cancer cells but also provides the essential cofactor (Zn2+) for signal amplification. This probe distinguishes cancer cells from normal cells in both cell lysates and living cells, demonstrating its potential application in the precision diagnosis of malignant tumors. Further investigations revealed that APE1 promoted the epithelial–mesenchymal transition in the TGF-β-induced model. In the hydrogen peroxide-induced oxidative stress model, moderate oxidative stress elevated APE1 activity and enhanced cell proliferation and migration, while excessive stress showed the opposite effect. These results establish the relationship between APE1 activity and cell behaviors in tumor metastasis and under oxidative stress and suggest that oxidative stress plays a complex role in the regulation of tumor metastasis.