An Integrated Sensing Disease Modeling Platform for In Situ Monitoring of Glutamate Neurotransmitter Using hiPSC-Derived Neurons and MNP@ZIF-8/ENZ

Glutamate, the main excitatory neurotransmitter, exhibits release imbalance associated with epilepsy, Down syndrome, and other disorders. However, limited human tissue, interspecies differences, and inadequate in situ detection hinder mechanistic studies and interventions for glutamatergic dysfunction. Here, we constructed an integrated glutamatergic neuron-MNP@ZIF-8/ENZ platform that combines hiPSC-based directional differentiation of glutamatergic neurons on the enzyme-modified sensing surface with in situ neurotransmitter detection. Owing to the high porosity and electrical conductivity of the MNP@ZIF-8 nanocomposite, the platform exhibited a linear range of 1–50   μM (R 2 = 0.999), a detection limit of 0.76   μM, and high selectivity against common interferents such as DA, 5-HT, and Glc. After seven days of cell culture, the sensor response current retention rate is approximately 90.1%. Notably, the integrated platform was applied to Down syndrome (DS) research, revealing that depolarization-evoked glutamate release from DS patient iPSC-derived glutamatergic neurons was only approximately 28% of that from normal controls, providing direct quantitative evidence of excitatory transmitter secretion deficit in DS. This integrated sensing disease modeling platform provides a personalized, reproducible, and scalable analytical tool for disease pathogenesis research and drug screening, representing a promising technological platform.