Xi Chen, J. Liu, Zhiyou Xiao, Guowei Wang, Yanfang Li, Hongwen Wu, Derong Xu
Solid-state nanopore sequencing, a key third-generation sequencing technology, offers considerable potential for genomics and diagnostics due to its long read lengths, real-time detection, and amplification-free operation. The technology identifies DNA sequences by measuring characteristic changes in ionic current as single-stranded DNA translocates through a nanoscale pore. However, its practical development faces challenges including limited spatiotemporal resolution, pore clogging from nonspecific adsorption, and significant electrical noise. This review systematically examines strategies developed to address these limitations. We discuss the use of ultrathin two-dimensional materials such as graphene and molybdenum disulfide to improve spatial resolution, and methods to modulate DNA translocation through optimized solution conditions, pore geometry, surface charge engineering, and bio-solid hybrid pore designs. Furthermore, we detail noise suppression strategies targeting key sources like thermal noise, 1/f noise, and dielectric noise. These approaches encompass careful material selection, surface coatings, innovations in chip and amplifier design, and machine learning-based signal processing. The review also outlines surface functionalization techniques that reduce clogging and enhance analytical specificity. While challenges remain, continued convergence of materials science, nanofabrication, and data science is advancing solid-state nanopore technology toward reliable, high-precision sequencing platforms, promising to significantly impact personalized medicine and biological research.