Tuning Core Flexibility and Curvature in Azine-Linked Covalent Organic Frameworks for Attomolar-Level Impedimetric Sensing of Glucose

Glucose serves as a key biomarker of metabolic health, requiring continuous and reliable monitoring. Nonenzymatic impedimetric sensors have emerged as a promising alternative to enzymatic glucose sensors, which dominate current clinical practice. However, their sensitivity is limited by weak molecular recognition and inefficient charge transport at the sensing interface. In this study, we tuned the core flexibility and curvature of azine-linked covalent organic frameworks (COFs) by substituting the central triazine ring in the C₃ symmetric building unit with a nitrogen atom. This modification maximized glucose-framework interactions, thereby enhancing signal transduction and detection sensitivity. The results confirmed the sensitivity and selectivity of the COFs toward glucose, with a linear response over a wide concentration range [1 aM-5 mM], surpassing previously reported glucose sensors. The sensors achieved a subattomolar limit of detection (LOD), with excellent stability and reproducibility compared to traditional enzymatic sensors, offering a simpler and more practical alternative for integration into wearable and implantable devices. Experimental findings are supported by molecular simulations, which reveals the mechanism of sensing and charge transfer dynamics. This work establishes a versatile design strategy for enzyme-free designed-to-purpose transducers, opening new pathways for ultrasensitive and selective molecular detection.