Precise regulation of endoplasmic reticulum (ER) stress signaling in cancer remains a central challenge for nucleic acid-based therapeutics, largely due to their inability to discriminate ER-stressed malignant cells and non-stressed normal cells. Here we report an ER stress-responsive regulatory platform that couples the disease-associated endoribonuclease activity of inositol-requiring enzyme 1 (IRE1) to the conditional activation of DNA-based effectors. By rationally grafting an X-box binding protein 1 (XBP1)-mimetic stem-loop "gate" onto canonical DNAzymes (IR-Dz), we generate constructs that remain catalytically inert under basal IRE1 activity but are activated upon ER stress-induced IRE1 cleavage. The resulting IR-Dz mediates cell-selective c-MYC silencing in ER-stressed cancer cells, thereby attenuating ER stress while sparing normal counterparts. Redirecting IR-Dz to IRE1 mRNA achieves the opposite outcome-self-silencing of IRE1 and amplification of ER stress in tumor cells. This modular architecture can be adapted to other nucleic-acid modalities, such as antisense oligonucleotides. By establishing IRE1 as an endogenous molecular trigger for spatially and contextually precise activation of nucleic acid effectors, our study introduces a general strategy for programmable, condition-dependent gene regulation and dynamic modulation of ER stress signaling in cancer.

Angew. Chem. Int. Ed. 2026, e2970755 http://dx.doi.org/10.1002/anie.2970755