DNA Framework‐Based Programmable Atom‐Like Nanoparticles for Non‐Coding RNA Recognition and Differentiation of Cancer Cells

Abstract The cooperative diagnosis of non‐coding RNAs (ncRNAs) can accurately reflect the state of cell differentiation and classification, laying the foundation of precision medicine. However, there are still challenges in simultaneous analyses of multiple ncRNAs and the integration of biomarker data for cell typing. In this study, DNA framework‐based programmable atom‐like nanoparticles (PANs) are designed to develop molecular classifiers for intra‐cellular imaging of multiple ncRNAs associated with cell differentiation. The PANs‐based molecular classifier facilitates signal amplification through the catalytic hairpin assembly. The interaction between PAN reporters and ncRNAs enables high‐fidelity conversion of ncRNAs expression level into binding events, and the assessment of in situ ncRNAs levels via measurement of the fluorescent signal changes of PAN reporters. Compared to non‐amplified methods, the detection limits of PANs are reduced by four orders of magnitude. Using human gastric cancer cell lines as a model system, the PANs‐based molecular classifier demonstrates its capacity to measure multiple ncRNAs in living cells and assesses the degree of cell differentiation. This approach can serve as a universal strategy for the classification of cancer cells during malignant transformation and tumor progression.