Scalable modulation of CRISPR‒Cas enzyme activity using photocleavable phosphorothioate DNA

Menglu Hu, Bingni Zhang, Yuanyue Shan, Feng Cao, Yihui Wang, Weiwei Qi, Xue Wang, Yuting Shen, Xinyi Guo, Mengmeng Zhang, Tian Tian, Wei Xie, Mingfeng Zhang (), Fang Liang (), Duanqing Pei () and Xiaoming Zhou ()
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Menglu Hu: South China Normal University
Bingni Zhang: South China Normal University
Yuanyue Shan: Chinese Academy of Sciences
Feng Cao: South China Normal University
Yihui Wang: South China Normal University
Weiwei Qi: South China Normal University
Xue Wang: South China Normal University
Yuting Shen: South China Normal University
Xinyi Guo: South China Normal University
Mengmeng Zhang: Westlake University
Tian Tian: South China Normal University
Wei Xie: Sun Yat-Sen University
Mingfeng Zhang: Westlake University
Fang Liang: South China Normal University
Duanqing Pei: Westlake University
Xiaoming Zhou: South China Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The regulation of CRISPR‒Cas activity is critical for developing advanced biotechnologies. Optical control of CRISPR‒Cas system activity can be achieved by modulation of Cas proteins or guide RNA (gRNA), but these approaches either require complex protein engineering modifications or customization of the optically modulated gRNAs according to the target. Here, we present a method, termed photocleavable phosphorothioate DNA (PC&PS DNA)-mediated regulation of CRISPR‒Cas activity (DNACas), that is versatile and overcomes the limitations of conventional methods. In DNACas, CRISPR‒Cas activity is silenced by the affinity binding of PC&PS DNA and restored through light-triggered chemical bond breakage of PC&PS DNA. The universality of DNACas is demonstrated by adopting the PC&PS DNA to regulate various CRISPR‒Cas enzymes, achieving robust light-switching performance. DNACas is further adopted to develop a light-controlled one-pot LAMP-BrCas12b detection method and a spatiotemporal gene editing strategy. We anticipate that DNACas could be employed to drive various biotechnological advances.

Date: 2025
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DOI: 10.1038/s41467-025-61094-5

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