Programmable Nanozyme Gating: A Molecular Ejector Switch (MES) for High-Fidelity miRNA-21 Sensing.

Nucleotide-level variants in miRNA or pathogen genomes can critically reprogram gene-regulatory networks or enhance disease severity, highlighting the urgent need for sensing platforms capable of resolving subtle sequence discrepancies. In this article, we present a programmable molecular ejector switch (MES) that functions as a confinement-gating smart nanozyme for adaptive nucleic-acid sensing. By integrating the etb topology of mesoporous Co-IRMOF-74-II with single-stranded DNA (ssDNA) gatekeepers, the MES transforms passive MOF scaffolds into an active logical device. Driven by the balance between van der Waals attraction and electrostatic repulsion, the ssDNA gatekeepers can be reversibly accommodated within the pores to block mass transport through the MES. Upon target binding, hybridization displaces the ssDNA gatekeeper, while the resulting rigid duplex is less compatible with pore re-entry, thereby restoring the overall nanozyme activity. As a proof of concept, the miRNA-21 sensor furnishes accurate colorimetric readouts (LOD: 0.84 nM; log-linear range 1-300 nM), while concurrent fluorescent signals (LOD: 0.10 nM; linear range 0.2-50 nM) cross-validate the gating logic. The sensor outputs exhibit a monotonic dependence on the mismatch degree, enabling high-fidelity discrimination of multi-nucleotide variants. This modular confinement-gating strategy is readily adaptable to other nucleic acid biomarkers, offering a versatile scaffold for the development of intelligent diagnostic devices.