Developing Solid-State Single-, Arrayed-, and Composite-Nanopore Sensors for Biochemical Sensing Applications

Ions, small molecules, and biomacromolecules are important components of the human body. They usually play important roles in various physiological and pathological events, showing a close relationship with human health. However, due to the ultralow concentrations of these substances and the presence of interfering chemicals, accurate and reliable measurement of these ions and molecules remains a huge challenge. Nanopore sensors, which combine nanofluidic and electrochemical technologies, have received a great deal of attention in recent years. Nanopore sensing is generally realized by measuring the electrochemical behaviors of ions in nanopores, which endows this technique with the advantages of high sensitivity, fast response, high sampling frequency, and experimental simplicity. In addition, owing to the confinement effect, the interaction between analytes and the nanopore is greatly enhanced, which can further improve the sensing sensitivity, even achieving single-entity analysis. With the development of materials science, micro/nanoprocessing technologies, and mass transport theories at the nanoscale, nanopore sensors have established themselves as a promising tool for the analysis of ions, biomolecules, and nanoparticles. Nanopore materials, as the core of nanopore sensors, can be classified into three categories based on the pore structure: single nanopores, arrayed nanopores, and composite nanopores. Single nanopores include two-dimensional (2D) material based single nanopores and glass/quartz nanopipettes. The single-pore structure can offer high sensitivity and spatial resolution, making single nanopores suitable for single-entity analysis. Arrayed nanopores consist of a large number of orderly arranged pores, generally including polymer nanopores and metal oxide nanopores. Arrayed-nanopore sensors possess advantages, including easy preparation, low cost, and high throughput, making them widely applicable in biochemical and environmental analysis. Composite nanopores, on the other hand, combine nanopores with other materials, such as conductive polymers and plasmonic metals, which can further enhance the sensitivity and accuracy of nanopore sensing. Through introducing recognition elements into these nanopores, the interaction between the analyte and the recognition elements can produce predictable changes in the nanopore properties, such as diameter, pore shape, surface charge, and wettability, resulting in readable changes in ion-current signals.

In this Account, we summarize the recent advancements in nanopore materials, nanopore-sensing mechanisms, and practical nanopore sensing applications, which are mainly based on work published by our group. We first briefly introduce single-, arrayed-, and composite-nanopore materials and their corresponding fabrication methods and then summarize the functionalization techniques employed to incorporate recognition sites within the nanopores. Then, we provide a glimpse of the fundamentals of nanopore sensing, including ion transport mechanisms and different nanopore sensing strategies. Whereafter, we present the recent advancements in practical applications of single-, arrayed-, and composite-nanopore sensors. Finally, we discuss the challenges and opportunities for improving the performance of nanopore sensors and provide an outlook on the future of this technique.