From signal transduction to visual response: a new paradigm empowered by tetrahedral DNA nanostructures

Schematic illustration of the TDN-driven paradigm shift: from intelligent multidimensional signal transduction to dynamic in vivo v isualization. TDN serve as a rigid scaffold to transform classical sensing models into cutting-edge logic computing, enabling precise in vitro signal quantification to address the question, ‘What is it?’. Furthermore, TDN act as ‘mobile platforms’ (e.g., via macrophage-hitchhiking) to actively traverse cellular and tissue barriers, ultimately achieving spatial localization of lesions to answer, ‘Where is it?’ • Rigid DNA frameworks optimize interface engineering to achieve high-fidelity signal transduction. • Tetrahedral DNA nanostructures transform biosensing from static detection to intelligent multidimensional logic computing. • These rigid scaffolds function as active mobile platforms to traverse biological barriers for deep-tissue visualization. Single-stranded signal probes, despite their ability to perform complex functions, are fundamentally limited by their susceptibility to degradation in biological fluids, which hinders effective signal transduction and quantitative target analysis. Furthermore, achieving accurate lesion localization in bioimaging is often impeded by the low cellular uptake efficiency, poor affinity, and limited tissue penetration of conventional imaging agents. Tetrahedral DNA nanostructures (TDN) have emerged as a groundbreaking platform to overcome these barriers, offering robust signal transduction and efficient delivery of targeted probes due to their inherent programmability, superior biostability, and powerful cell membrane permeability. This review first analyzes how TDN optimize classical sensing strategies (electrochemical, optical, electrochemiluminescence) for accurate in vitro quantification. We then explore the evolution toward TDN-empowered logic computing and multidimensional sensing, enabling intelligent molecular decision-making. Subsequently, we elucidate the translation of these principles into TDN-mediated cross-biological barrier responses for in vivo visualization, detailing the imaging progression to systemic localization and dynamic functional programming for biosystem regulation. Finally, we provide a forward-looking perspective on the translational pathway of these complex systems from proof-of-concept studies to preclinical and clinical realization.