Core-Shell-Shell Upconversion Nanoparticles with Enhanced Emission for Wireless Optogenetic Inhibition

Recent advances in upconversion technology have enabled optogenetic neural stimulation using remotely applied optical signals, but limited success has been demonstrated for neural inhibition by using this method, primarily due to the much higher optical power and more red-shifted excitation spectrum that are required to work with the appropriate inhibitory opsin proteins. To overcome these limitations, core-shell-shell upconversion nanoparticles (UCNPs) with a hexagonal phase are synthesized to optimize the doping contents of ytterbium ions (Yb3+) and to mitigate Yb-associated concentration quenching. Such UCNPs emission contains an almost three-fold enhanced peak around 540-570 nm, matching the excitation spectrum of a commonly used inhibitory opsin protein, halorhodopsin. The enhanced UCNPs are utilized as optical transducers to develop a fully implantable upconversion-based device for in vivo tetherless optogenetic inhibition, which is actuated by near-infrared (NIR) light irradiation without any electronics. When the device is implanted into targeted sites deep in the rat brain, the electrical activity of the neurons is reliably inhibited with NIR irradiation and restores to normal level upon switching off the NIR light. The system is further used to perform tetherless unilateral inhibition of the secondary motor cortex in behaving mice, achieving control of their motor functions. This study provides an important and useful supplement to the upconversion-based optogenetic toolset, which is beneficial for both basic and translational neuroscience investigations.