DNA-based programmable gate arrays for general-purpose DNA computing

• Published in: Nature (London) Vol. 622; no. 7982; pp. 292 - 300
• Main Authors: Lv, Hui, Xie, Nuli, Li, Mingqiang, Dong, Mingkai, Sun, Chenyun, Zhang, Qian, Zhao, Lei, Li, Jiang, Zuo, Xiaolei, Chen, Haibo, Wang, Fei, Fan, Chunhai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2023; Nature Publishing Group
• Subjects: 119/118; 14; 38; 38/77; 639/638/541/966; 639/925/926/1047; Analog to digital converters; Circuit design; Computation; Deoxyribonucleic acid; Design; DNA; Field programmable gate arrays; Gate arrays; Humanities and Social Sciences; Integrated circuits; Liquid phases; Logic; miRNA; multidisciplinary; Multilayers; Oligonucleotides; Quadratic equations; Reconfiguration; Science; Science (multidisciplinary); Signal transduction
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06484-9

The past decades have witnessed the evolution of electronic and photonic integrated circuits, from application specific to programmable 1 , 2 . Although liquid-phase DNA circuitry holds the potential for massive parallelism in the encoding and execution of algorithms 3 , 4 , the development of general-purpose DNA integrated circuits (DICs) has yet to be explored. Here we demonstrate a DIC system by integration of multilayer DNA-based programmable gate arrays (DPGAs). We find that the use of generic single-stranded oligonucleotides as a uniform transmission signal can reliably integrate large-scale DICs with minimal leakage and high fidelity for general-purpose computing. Reconfiguration of a single DPGA with 24 addressable dual-rail gates can be programmed with wiring instructions to implement over 100 billion distinct circuits. Furthermore, to control the intrinsically random collision of molecules, we designed DNA origami registers to provide the directionality for asynchronous execution of cascaded DPGAs. We exemplify this by a quadratic equation-solving DIC assembled with three layers of cascade DPGAs comprising 30 logic gates with around 500 DNA strands. We further show that integration of a DPGA with an analog-to-digital converter can classify disease-related microRNAs. The ability to integrate large-scale DPGA networks without apparent signal attenuation marks a key step towards general-purpose DNA computing. Generic single-stranded oligonucleotides used as a uniform transmission signal can reliably integrate large-scale DNA integrated circuits with minimal leakage and high fidelity for general-purpose computing.