Neurofluid Biomarker Sensors: Integrated Design Strategies From Molecular Recognition to Precision Neurological Diagnosis

ABSTRACT

The occurrence, progression, and treatment of neurological diseases are accompanied by complex humoral chemical changes, including ion imbalances, neurotransmitter disturbances, metabolic abnormalities, and abnormally elevated levels of inflammatory factors and pathological proteins. These molecular dynamics often precede the onset of clinical symptoms. Therefore, real‐time and accurate monitoring of these neurofluid biomarkers is crucial for early disease diagnosis, efficacy evaluation, and mechanistic research. However, the cerebrospinal fluid, interstitial fluid, and brain tissue microenvironment are complex, including factors such as low target molecule content, rapid changes in the microenvironment, strong background interference, and the risk of tissue damage, making neurofluid monitoring extremely challenging and thus driving the development of various advanced sensing technologies. Unlike previous reviews that primarily focused on single sensor modalities or specific biomarker classes, this review uniquely integrates the transducer‐based classifications (electrochemical, optical, mechanical, and multimodal platforms) in neurofluid sensing technologies and design strategies driven by different classes of neurofluid biomarkers (ions, neurotransmitters, metabolites, and inflammatory proteins). Furthermore, this review summarizes the challenges and future development directions of neurofluid sensors, providing a comprehensive and interdisciplinary framework aimed at offering a systematic reference and future development guidance for promoting the development of intelligent, highly sensitive, and clinically translatable neurofluid sensing technologies.