Fragment-Imprinted Synergistic Copper Ion-Bridged Silver Nanocomposites Unlock Signal Activation for Picomolar-Level Sensing of <scp>l</scp> -Histidine

l-Histidine (l-His), as a semiessential amino acid in the human body, plays a crucial role in maintaining normal physiological functions, and abnormal levels of l-His may lead to the occurrence of various diseases. Therefore, achieving an ultrasensitive sensing interface for l-His is of critical importance for the clinical diagnosis and treatment of related diseases. Currently, the signal conduction mode of a molecularly imprinted electrochemical sensing interface for l-His mainly relies on the electrochemical activity of the target itself or changes in electrical signals caused by alterations in the impedance of the sensing interface. However, the two modes are limited by the weak electrochemical activity of the target itself and the susceptibility of the sensing interface to nonspecific adsorption interference, resulting in reduced sensitivity and selectivity of the sensing interface. Herein, a fragment-imprinted synergistic unlocking signal amplification activation strategy based on the probe labeling mode is proposed. Utilizing copper ion (Cu²⁺)-bridged silver nanoparticles ((AgNP-l-Cys-Cu²⁺)_n), a (AgNP-l-Cys-Cu²⁺)_n nanocomposite signal amplification probe is designed to label l-His fixed in fragment-molecularly imprinted polymers (F-MIP) through strong coordination, achieving ultrasensitive and specific electrochemical detection of l-His. The sensing interface can recognize l-His at the picomolar level, and the imprinting factor reached 6.74. This strategy provides a rational route to improve the performance of the MIP electrochemical sensing interfaces.