Topological barrier to Cas12a activation by circular DNA nanostructures facilitates autocatalysis and transforms DNA/RNA sensing

Fei Deng, Yi Li (), Biyao Yang, Rui Sang, Wei Deng, Maya Kansara, Frank Lin, Subotheni Thavaneswaran, David M. Thomas and Ewa M. Goldys
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Fei Deng: University of New South Wales
Yi Li: University of New South Wales
Biyao Yang: University of New South Wales
Rui Sang: University of New South Wales
Wei Deng: University of Technology Sydney
Maya Kansara: Garvan Institute of Medical Research, Darlinghurst
Frank Lin: Garvan Institute of Medical Research, Darlinghurst
Subotheni Thavaneswaran: Garvan Institute of Medical Research, Darlinghurst
David M. Thomas: Garvan Institute of Medical Research, Darlinghurst
Ewa M. Goldys: University of New South Wales

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Control of CRISPR/Cas12a trans-cleavage is crucial for biosensor development. Here, we show that small circular DNA nanostructures which partially match guide RNA sequences only minimally activate Cas12a ribonucleoproteins. However, linearizing these structures restores activation. Building on this finding, an Autocatalytic Cas12a Circular DNA Amplification Reaction (AutoCAR) system is established which allows a single nucleic acid target to activate multiple ribonucleoproteins, and greatly increases the achievable reporter cleavage rates per target. A rate-equation-based model explains the observed near-exponential rate trends. Autocatalysis is also sustained with DNA nanostructures modified with fluorophore-quencher pairs achieving 1 aM level (

Date: 2024
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DOI: 10.1038/s41467-024-46001-8

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