Highly specific aptamer-based structure-switching sensor for detection of the smallest alkali metal ion Li⁺ in serum

Lithium carbonate, a frontline drug for bipolar disorder (BD), requires strict therapeutic drug monitoring (TDM) due to its narrow therapeutic window (0.6-1.2 mM). Existing methods like inductively coupled plasma mass spectrometry (ICP-MS) and ion-selective electrodes (ISE) struggle to balance point-of-care testing (POCT) demands with interference in complex matrices. Here, we isolated a highly specific Li⁺ DNA aptamer (Li-1) via a Capture-SELEX strategy and constructed a sensitive structure-switching fluorescent sensor. Isothermal titration calorimetry (ITC) and circular dichroism (CD) spectroscopy were utilized to perform thermodynamic and structural analyses of its molecular recognition process, revealing that the binding of Li-1 to Li⁺ is dominated by an "enthalpy-driven" conformational rearrangement. Based on a 5-carboxyfluorescein (FAM)-labeled DNA strand displacement strategy, the established sensor achieved a dynamic linear response of 6.2 - 60 μM with a limit of detection (LOD) of 1.8 μM. It exhibited no obvious cross-recognition to Na⁺, K⁺, Ca²⁺, and Mg²⁺. The spiked recovery rates ranged from 88.76% to 102.33%. In double-blind tests of clinical BD patient serum, the method showed strong statistical agreement (Pearson's r > 0.92) with the clinical gold standard ICP-MS. This work develops a DNA aptamer targeting the smallest alkali metal ion, Li⁺, providing a highly specific and sensitive method for POCT blood lithium monitoring in psychiatric practice.