Endogenous enzyme-activatable catalytic DNA nanodevice for cancer cell-selective piRNA imaging and regulation

Abstract

As the newly identified epigenetic regulators, piwi-interacting RNAs (piRNAs) are garnering increasing attention due to their potential implications in tumorigenesis. However, cancer cell-selective detection and regulation of cancer-associated piRNAs remains a significant challenge because of their broad distribution in both malignant and normal cells. Herein, we develop an endogenous enzyme-activatable catalytic DNA nanodevice (EE-CDN) for cell-selective imaging and regulation of piRNA. The EE-CDN remains inert in normal cells, which minimizes nonspecific background signal and avoids unwanted side effects. The EE-CDN can be activated only in cancer cells to enable cell-specific piRNA recognition. By anchoring the sensing elements onto a tetrahedral DNA scaffold, the EE-CDN allows amplified detection of piRNA with accelerated kinetics via spatially confined catalytic DNA assembly. Taking advantage of single-molecule detection, the EE-CDN can achieve attomolar sensitivity, enabling accurate discrimination and molecular subtyping of breast cancer in both cellular models and clinical tissue specimens. Importantly, the EE-CDN can facilitate in vivo tracking of piRNA in living breast cancer cells and breast cancer-bearing mice with superior spatial specificity, and it can efficiently suppress tumor growth in cells and mice models via depletion of endogenous piRNA, offering a powerful platform for precise diagnosis of cancer and targeted therapy.