Xie, Z.; Pan, L.; Hua, Y.; Hou, B.; Xiang, P.; Wu, Y.; Shan, S.; Yan, X.; Chen, Y.; Gao, P.; Du, J.; Liu, J.

Modulating neuronal activity with light is a powerful tool for neuroscience research. However, currently available technologies often require invasive fibers for delivery of visible light, causing tissue damage and limiting behavioral studies. Although near-infrared (NIR) neuronal modulation improves tissue penetration depth, sustained NIR illumination during neuromodulation raises significant concerns about photothermal effects. Here, we introduce a dual-wavelength near-infrared switch (Dual-NIR Switch) that uses two transcranial NIR inputs to initiate and terminate neuronal activation, enabling tether-free neuromodulation in freely moving mice. Dual-NIR Switch employs orthogonal dichromatic upconversion nanoparticles that emit blue and green light under 980 nm and 808 nm excitation, respectively, to activate and inactivate the step-function opsin SOUL. Therefore, transient 980nm NIR illumination initiates neuronal excitation, which will remain excited without further stimulation but will be rapidly terminated on demand by a subsequent 808nm illumination. Upon transcranial 980nm and 808nm NIR illuminations in freely moving mice, we achieve on-demand control of behavioral paradigms across tunable timescales, ranging from seconds to minutes and even extending to sub-hour durations. By eliminating the need for sustained NIR irradiation, Dual-NIR Switch offers an on-demand, duration-tunable neuromodulation tool for both basic neuroscience and potential therapeutic applications in treating brain diseases.