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Published on: April 24, 2021
Bioinspired Molecular Engineering of IRE1-Gated DNAzymes for Self-Adaptive Bidirectional Modulation of ER Stress
Chuangui Sheng1,2, Jian Zhao1,2, Nan Liu1,2
1CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
Abstract:
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.
Insights
This study introduces a novel nucleic acid platform that precisely targets cancer cells by responding to endoplasmic reticulum (ER) stress. This approach enables selective gene silencing in tumors while sparing healthy cells, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Endoplasmic reticulum (ER) stress signaling is crucial in cancer, but precise therapeutic targeting remains challenging.
- Current nucleic acid therapeutics struggle to differentiate between stressed cancer cells and normal cells.
Purpose of the Study:
- To develop an ER stress-responsive regulatory platform for precise nucleic acid-based cancer therapeutics.
- To engineer constructs that conditionally activate in response to ER stress-induced inositol-requiring enzyme 1 (IRE1) activity.
Main Methods:
- Grafting an X-box binding protein 1 (XBP1)-mimetic stem-loop onto DNAzymes (IR-Dz) to create ER stress-responsive constructs.
- Utilizing IRE1 cleavage for conditional activation of DNAzymes.
- Adapting the modular architecture for other nucleic acid modalities like antisense oligonucleotides.
Main Results:
- The developed IR-Dz constructs are catalytically inert under basal IRE1 activity but activate upon ER stress-induced IRE1 cleavage.
- IR-Dz mediates cell-selective c-MYC silencing in ER-stressed cancer cells, reducing ER stress and sparing normal cells.
- Redirecting IR-Dz to IRE1 mRNA results in IRE1 self-silencing and amplified ER stress in tumor cells.
Conclusions:
- Established IRE1 as an endogenous molecular trigger for precise, context-dependent activation of nucleic acid effectors.
- Introduced a general strategy for programmable, condition-dependent gene regulation.
- Demonstrated dynamic modulation of ER stress signaling in cancer therapeutics.
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