Highly Sensitive Diagnosis of Extracellular Calcium Ions Associated Brain Diseases using Ca2+‐Dependent T2‐T1 Switchable Magnetic Nanosensors

Abstract Calcium ions (Ca 2+ ) play crucial roles as second messengers in living cells and are associated with the onset and development of chronic brain diseases, including epilepsy. Dynamic and real‐time imaging of extracellular calcium levels ([Ca 2+ ] ex ) in the brain holds great potential for identifying disease foci. Magnetic resonance imaging (MRI) is a powerful non‐invasive tool for Ca 2+ imaging with unlimited depth penetration. However, current available Ca 2+ MR sensors lack the sensitivity to monitor small [Ca 2+ ] ex alterations associated with chronic brain diseases in vivo. In this study, a highly sensitive Ca 2+ ‐dependent T2‐T1 switchable magnetic nanosensor is reported, consisting of Ca 2+ ‐specific ligands engineered near‐paramagnetic iron oxide nanoparticles. Surface ligand modifications can be adjusted to regulate the interaction energy between sensors and Ca 2+ , allowing for customizable response range and sensitivity to fulfill the in vivo imaging requirements. The optimized sensors enable non‐invasive visualization of early‐stage seizure focus in mice undergoing epilepsy.