Near-Infrared-II Chemo-Optogenetics for Deep-Brain Stimulation

ABSTRACT Precise activation of ion channels enables fine-tuned control of neuronal excitability, providing a powerful strategy for dissecting and modulating neural circuits. Although optogenetics offers high spatiotemporal neuronal manipulation with cell-type specificity, its reliance on visible light (400-650 nm) limits tissue penetration to millimeter depths, restricting applications in deep-brain stimulation. Here we report a near-infrared-II (NIR-II)-sensitive calcium channel, HaloNeu, created by genetically fusing a circularly permuted HaloTag (cpHaloTag) to the thermo-sensitive transient receptor potential vanilloid 1 (TRPV1) and covalently conjugating NIR-II photothermal nanotransducers (HPN). The HaloNeu enables non-invasive neuromodulation at depths up to 1.0 cm at ultralow laser power (∼60 mW/cm2) and up to 5.0 cm under the safe exposure limit (∼1 W/cm2) with 1064 nm laser illumination. Remarkably, HaloNeu maintains stable, on-demand neuron-specific modulation for over two months in vivo, providing sustained activation of ventral tegmental area (VTA) circuits and effective alleviation of Parkinsonian symptoms in mouse models. These results establish HaloNeu as a robust and versatile platform for cell-type-specific, deep-tissue, and chronic neuromodulation, with broad implications for neuroscience and neurotherapeutics. Competing Interest Statement The authors have declared no competing interest.