期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：5
DOI：10.1073/pnas.2112812119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Detection of molecular interactions is the foundation for many important biotechnology applications in society and industry, such as drug discovery, diagnostics, and DNA sequencing. This report describes a broadly applicable platform for detecting molecular interactions at the single-molecule scale, in real-time, label-free, and potentially highly multiplexable fashion, using single-molecule sensors on a highly scalable semiconductor sensor array chip. Such chips are both practically manufacturable in the near term, and have a durable long-term scaling roadmap, thus providing an ideal way to bring the power of modern chip technology to the broad area of biosensing. This work also realizes a 50-year-old scientific vision of integrating single molecules into electronic chips to achieve the ultimate miniaturization of electronics.
For nearly 50 years, the vision of using single molecules in circuits has been seen as providing the ultimate miniaturization of electronic chips. An advanced example of such a molecular electronics chip is presented here, with the important distinction that the molecular circuit elements play the role of general-purpose single-molecule sensors. The device consists of a semiconductor chip with a scalable array architecture. Each array element contains a synthetic molecular wire assembled to span nanoelectrodes in a current monitoring circuit. A central conjugation site is used to attach a single probe molecule that defines the target of the sensor. The chip digitizes the resulting picoamp-scale current-versus-time readout from each sensor element of the array at a rate of 1,000 frames per second. This provides detailed electrical signatures of the single-molecule interactions between the probe and targets present in a solution-phase test sample. This platform is used to measure the interaction kinetics of single molecules, without the use of labels, in a massively parallel fashion. To demonstrate broad applicability, examples are shown for probe molecule binding, including DNA oligos, aptamers, antibodies, and antigens, and the activity of enzymes relevant to diagnostics and sequencing, including a CRISPR/Cas enzyme binding a target DNA, and a DNA polymerase enzyme incorporating nucleotides as it copies a DNA template. All of these applications are accomplished with high sensitivity and resolution, on a manufacturable, scalable, all-electronic semiconductor chip device, thereby bringing the power of modern chips to these diverse areas of biosensing.
