Implementing complex nucleic acid circuits in living cells

• DOI: 10.1126/sciadv.adv6512
• Publication Date: 2025-05-01T02:03:58Z
• Authors: Jiajia Sun; Xiewei Xiong; Wei Lai; Zhongdong Wu; Heming Wang; Lei Yang; Niannian Xue; Qunyan Yao; Guangqi Song; Yicheng Zhao; Li Li; Fei Wang; Chunhai Fan; Hao Pei

Synthetic nucleic acid-based computing has demonstrated complex computational capabilities in vitro. However, translating these circuits into living cells remains challenging because of instability and cellular interference. We introduce an allosteric strand exchange (ASE) strategy for intracellular computing. Leveraging conformational cooperativity to regulate exchange, ASE offers a modular platform designing with flexible programmability. engineer scalable circuit architecture based on that can execute AND OR logic scale eight-input expression. demonstrate ASE-based detect messenger RNAs high specificity mammalian via computation. The capacity accept as inputs enables integration endogenous information efficient multi-input processing, by molecular classifier monitoring key cell reprogramming events. Reprogramming interface CRISPR-Cas9 programmable control Cas9-targeting activity gene editing, highlighting their potential advancing biocomputation.