NIR Biosensing of Neurotransmitters in Stem Cell‐Derived Neural Interface Using Advanced Core–Shell Upconversion Nanoparticles

Nondestructive neurotransmitter detection and real-time monitoring of stem cell differentiation are both of great significance in the field of neurodegenerative disease and regenerative medicine. Although luminescent biosensing nanoprobes have been developed to address this need, they have intrinsic limitations such as autofluorescence, scattering, and phototoxicity. Upconversion nanoparticles (UCNPs) have gained increasing attention for various biomedical applications due to their high photostability, low auto-fluorescent background, and deep tissue penetration; however, UCNPs also suffer from low emission intensities due to undesirable energy migration pathways. To address the aforementioned issue, a single-crystal core-shell-shell "sandwich" structured UCNP is developed that is designed to minimize deleterious energy back-transfer to yield bright visible emissions using low power density excitations. These UCNPs show a remarkable enhancement of luminescent output relative to conventional β-NaYF4:Yb,Er codoped UCNPs and β-NaYF4:Yb,Er@NaYF4:Yb "active shell" alike. Moreover, this advanced core-shell-shell UCNP is subsequently used to develop a highly sensitive biosensor for the ultrasensitive detection of dopamine released from stem cell-derived dopaminergic-neurons. Given the challenges of in situ detection of neurotransmitters, the developed NIR-based biosensing of neurotransmitters in stem cell-derived neural interfaces present a unique tool for investigating single-cell mechanisms associated with dopamine, or other neurotransmitters, and their roles in neurological processes.