Macrocycle-mediated supramolecular regulation of signal transduction in nanoscale biosensors.

This Feature Article reviews macrocycle-mediated signal transduction in nanoscale biosensors from the perspective of recognition-induced physicochemical perturbations. Signal transduction in nanoscale biosensors is traditionally categorized according to device architectures or signal outputs, including electrochemical, optical, plasmonic, and field-effect platforms. While effective from an engineering perspective, such classifications often obscure the common molecular events that ultimately govern sensing responses. Here, we propose a unified supramolecular framework that connects macrocycle-mediated molecular recognition with diverse signal transduction processes through recognition-induced physicochemical perturbations at nanoscale interfaces. Focusing on representative advances reported since 2019, we systematically examine four major perturbation modes: interfacial charge perturbation, molecular spatial perturbation, interfacial local-field perturbation, and supramolecular network perturbation. From this perspective, seemingly disparate sensing modalities can be interpreted as different physical manifestations of recognition-induced perturbations. We further discuss how macrocyclic hosts regulate interfacial charge transport, molecular organization, local electromagnetic environments, and supramolecular network architectures, while critically considering coupled mechanisms, mechanistic limitations, and challenges associated with practical sensing applications. By shifting the focus from sensing outputs to perturbation origins, this review provides a unified mechanistic framework for understanding macrocycle-mediated signal transduction and offers guidance for the rational design of more robust supramolecular biosensors.