Nongenetic <i>in Vivo</i> Bimodal Neuromodulation via Photothermal Gold Nanorods and a Multifunctional Fiber Neural Probe.

Abstract

Neuromodulation is central to both fundamental neuroscience and the development of next-generation brain-computer interfaces (BCIs). However, most cell-type-specific neuromodulation strategies rely on genetic approaches such as optogenetics, which, despite their high spatiotemporal precision, can perturb intrinsic neuronal properties and raise concerns regarding off-target effects and gene-expression efficiency, thereby limiting clinical translation. Moreover, achieving true bimodal neuromodulation remains challenging, as single-gene expression typically enables either inhibition or excitation, restricting applications to one-way perturbations rather than bimodal control of neural activity. Here, we establish a nongenetic bimodal neuromodulation platform by integrating cholesterol-functionalized gold nanorods (GNR-CLS) with a multifunctional fiber-based neural (MFN) probe for localized photothermal stimulation and validate its functionality in the mouse brain. The MFN probe combines microfluidic delivery, near-infrared (NIR) light transmission, and electrophysiological recording within a single flexible fiber, enabling submillimeter colocalization of nanoparticles and optical stimuli with electrophysiological verification of photothermal neuromodulation. Using this platform, we demonstrate <i>in vivo</i> bimodal neuromodulation with both inhibitory and excitatory neuronal responses. Specifically, continuous NIR irradiation suppresses spontaneous firing of GNR-CLS-treated CA1 neurons via activation of thermosensitive inhibitory ion channels, whereas high-intensity NIR pulses delivered to the medial entorhinal cortex elicit spiking activity in the downstream dentate gyrus by transient modulation of membrane capacitance. Neuronal responses are governed by optical pulse parameters, with pulse width and frequency dictating a reversible transition of inhibitory and excitatory neuromodulation. Together, these results demonstrate a fully nongenetic approach to bimodal neuromodulation, enabling both excitatory and inhibitory neuronal control through optical parameter tuning alone.