Detection of Analytes with the Outer Surface of Solid-State Nanochannels: From pm to μm

Accurately simulating or sensitively monitoring specific substances, such as ions, molecules, and proteins in the life process, is essential for gaining a fundamental comprehension of the underlying biological mechanism, which has been a trending topic for many years. Solid-state nanochannels, inspired by biological ion channels, have been developed for decades and have achieved significant success, representing the forefront of the interdisciplinary fields of bioanalytical chemistry and nanotechnology. Typically, solid-state nanochannels with a pore size of less than 100 nm are selected to construct nanochannel-based biosensors, which can be an excellent platform to analyze small analytes, such as ions and small molecules, in a restricted space and simulate the intricate process of ion transport in living organisms. Furthermore, by integrating functional components that are termed probes into artificial devices, the nanochannel system has emerged as a remarkable tool for label-free and highly sensitive detection in practical applications. Nonetheless, the detection of large substances (more than nanoscale in size) has consistently posed a significant challenge, since previous research on solid-state nanochannels has mainly concentrated on the contribution of probes at the inner wall, which requires the biotargets to enter the nanochannel for successful detection. Moreover, the lack of testing techniques for the chemical and physical properties of probes anchored deep inside confined nanochannels results in an unclear working mechanism, which is another issue that cannot be ignored. The requirement for a more efficient and extensive detection platform has spurred an in-depth study of nanochannels, which provides innovative insight concentrating on the less restricted space on the outer surface (OS) of nanochannels and the probes at the OS (P_OS).In this Account, several approaches to constructing the OS and modifying P_OS are briefly summarized. Subsequently, ultrasensitive detection of analytes across a range of sizes, encompassing not only the ions and small molecules from ∼100 pm to ∼2 nm but also the large substances from ∼2 nm to ∼20 μm through the use of P_OS in the last five years, is introduced. Through the characterization of OS and the precise control of P_OS, the sensing mechanism, including surface charge and wettability, with P_OS is discussed unambiguously. Additionally, an intelligent model using dual-signal responses such as electrical and optical to enhance the responsiveness and accuracy of quantitative analysis is discussed, which can distinguish the conformation of an analyte by the exposed single cysteine thiol group. We expect that this timely Account will offer instructive insights into the development of a nanochannel-based platform to facilitate the analysis of biomolecules of varying sizes.