Ultrasmall Superparamagnetic Magnetite Nanoparticles as Glutamate-Responsive Magnetic Resonance Sensors

Glutamate, the primary excitatory neurotransmitter in the central nervous system, plays a pivotal role in synaptic signaling, learning, and memory. Abnormal glutamate levels are implicated in various neurological disorders, including epilepsy, Alzheimer's disease, and ischemic stroke. Despite the utility of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in diagnosing such conditions, the development of effective glutamate-sensitive contrast agents remains a challenge. In this study, we present ultrasmall, citric acid-coated superparamagnetic iron oxide nanoparticles (CA-SPIONs) as highly selective and sensitive MRS probes for glutamate detection. These 5 nm magnetite CA-SPIONs exhibit a stable dispersion in physiological buffers and undergo aggregation in the presence of glutamate, significantly enhancing the T₂ MRS contrast power. At physiological glutamate levels, the CA-SPIONs yielded a pronounced signal change ratio of nearly 60%, while showing a negligible response to other neurotransmitters such as GABA and dopamine. Computational simulations confirmed the mechanism of glutamate-mediated aggregation and its impact on transversal relaxation rates and relaxivities. The sensitivity and selectivity of CA-SPIONs underscore their potential as eco-friendly, iron-based alternatives for future neurological sensing applications targeting glutamatergic dysfunction.