Programmable targeted RNA degradation via dCas13d-directed chaperone-mediated autophagy (dCasCMA)

Hui-Ping Wen, Cong Yu, Shuli Bi, Lin-Han Jiang, Zhi-Gang Wang, Zhuhua Yao, Dai-Wen Pang and Shu-Lin Liu ()
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Hui-Ping Wen: Nankai University, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, Frontiers Science Center for Cell Responses, College of Chemistry
Cong Yu: Nankai University, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, Frontiers Science Center for Cell Responses, College of Chemistry
Shuli Bi: Nankai University, School of Medicine
Lin-Han Jiang: Nankai University, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, Frontiers Science Center for Cell Responses, College of Chemistry
Zhi-Gang Wang: Nankai University, School of Medicine
Zhuhua Yao: The First Affiliated Hospital of Nankai University, Department of Cardiology, Tianjin Union Medical Center
Dai-Wen Pang: Nankai University, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, Frontiers Science Center for Cell Responses, College of Chemistry
Shu-Lin Liu: Nankai University, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Centre for New Organic Matter, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Centre for Analytical Sciences, Frontiers Science Center for Cell Responses, College of Chemistry

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract RNA-targeted degradation technologies offer significant promise for treating diseases by selectively disrupting gene expression. However, a robust method to specifically, efficiently, and programmability degrade targeted RNAs in mammalian cells is still in demand. Here, we present a versatile platform, dCas13d-directed chaperone-mediated autophagy (dCasCMA), which integrates the precise targeting capabilities of dCas13/CRISPR with the degradation efficiency of chaperone-mediated autophagy (CMA) to achieve efficient degradation of specific RNAs. By combining dCas13d with a CMA-targeting motif and customizable guide RNA (gRNA), the platform allows for accurate targeting of both exogenous and endogenous RNAs in cells. Moreover, the incorporation of multiplexed gRNA expression arrays enables the simultaneous degradation of multiple RNA targets during viral pathogenesis in live cells and in vivo. Our findings emphasize the platform’s modular design, which enables flexible combinations of dCCTM components with user-defined gRNA sequences. This versatility positions it as a promising tool for developing innovative therapies for various diseases.

Date: 2025
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DOI: 10.1038/s41467-025-65768-y

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