Multidimensional signal amplification architectures in electrochemical immunosensing integrate porous nanomaterials, biocatalysis, and nucleic acid circuits to achieve attomolar detection

Abstract

Electrochemical immunosensors have significantly advanced point-of-care diagnostics and environmental monitoring, owing to their high specificity, portability, and compatibility with miniaturized systems. Nevertheless, their detection sensitivity remains limited by the ultralow concentrations of target analytes (such as disease biomarkers, pathogens, or environmental contaminants), creating an urgent need for innovative signal amplification strategies to meet practical and regulatory demands. This review presents a systematic overview of emerging signal amplification strategies, placing a dedicated focus on covalent organic frameworks (COFs) and metal–organic frameworks (MOFs) as highly promising yet underexplored nanomaterials. Although traditional materials such as carbon nanotubes (CNTs), graphene, enzyme cascades, and DNA-based systems have been widely investigated in electrochemical immunosensing, COFs and MOFs have attracted comparatively less attention despite their exceptional properties. Beyond summarizing the well-established porous materials, this work delves into the distinctive roles of COF and MOF architectures in promoting electron transfer, increasing immobilization capacity, and strengthening signal amplification. A comparative analysis is provided, aligning these emerging frameworks with conventional amplification approaches, including enzymatic reactions, DNA nanotechnology, and affinity-based methods. A primary objective of this review is to highlight recent mechanistic breakthroughs and innovative applications of COFs and MOFs that remain underrepresented in existing literature. Additionally, persistent challenges such as real-sample matrix effects, multiplex detection, and sensor regeneration are discussed. We conclude with prospective research directions, incorporating advancements in microfluidics, reusable interfaces, and artificial intelligence-assisted design, to pave the way toward scalable and high-performance immunosensing platforms.