Enzyme‐Activated Programmable Theranostic Platform for Spatiotemporal Imaging of Intracellular MicroRNA and On‐Demand Manipulation‐Mediated Therapy

ABSTRACT Imaging the aberrant expression of a single microRNA (miRNA) in living cells is often inadequate for accurately evaluating pathological states or implementing responsive therapies. It is a critical need for advanced molecular tools capable of spatiotemporally sensing miRNA and other biomarkers, accompanying the on‐demand therapeutic functions. Here, we present a miRNA molecular strategy, enabling both biomarker detection and biomarker‐driven therapy. In this platform, a Cy3‐labeled hairpin reporter (EH1) containing an apurinic/apyrimidinic endonuclease 1 (APE1) recognition unit, along with a Cy5‐labeled hairpin (H2), is co‐loaded onto the cerium‐based metal–organic framework (Ce‐MOF) in a precisely controlled manner (Ce‐MOF/DNA). Upon internalization in tumor cells characterized by the elevated levels of carcinogenic APE1 and miRNA‐21, the Ce‐MOF/DNA theranostic system is activated. APE1 and miRNA‐21 function as endogenous activators that trigger the hybridization chain reaction (HCR), leading to fluorescent resonance energy transfer (FRET) between Cy3 and Cy5, which provides a reliable readout for evaluating disease conditions in real‐time. Moreover, the Ce‐MOF/DNA system exerts therapeutic effects by upregulating the tumor suppressor gene PTEN and inhibiting the oncogenic functions of miRNA‐21, thereby suppressing tumor growth. This approach may pave the way for precise diagnosis and effective treatment for cancers characterized by dysregulated miRNA expression.