Precise neuromodulation is essential for exploring neural mecha-nisms and improving treatments for neurological disorders.While conventional electrical implants provide effective stimulation, their invasiveness often leads to tissue damage, infection, andscarring, creating a demand for less invasive alternatives. Opticalstimulation has emerged as a promising solution in animal models, affording high spatiotemporal resolution and the ability totarget specific neuron subtypes. Among these methods, optogenet-ics has been revolutionary, which uses light to control neural activi-ties through light-sensitive microbial opsins expressed in specificneurons. However, optogenetics faces two major challenges: (i) theuse of visible light, which is scattered and absorbed strongly in bio-logical tissues, necessitating implanted optical fibers for deep-brainstimulation, causing the same tissue damage seen with electrical im-plants , and (ii) the intrinsic need for genetic modification, which introduces delays of several weeks post–viral deliv-ery for full opsin expression and limits clinical translation.To address these limitations, researchers have explored solutions intwo key areas. First, to overcome light penetration challenges, recentapproaches include the development of red-shifted opsins responsive tolonger wavelengths , the use of upconversion nanoparticles (UCNPs) that convert near-infrared (NIR) light into shorter wavelengths and thermogenetics involving heat-sensitive ion channels. However, these techniques still rely on genetic modificationand complex molecular designs , limiting their immediacyand broader applicability across neuron populations. Second, effortsto bypass genetic modification have led to nongenetic optical neuro-modulation techniques, which use transducers to convert light intoacoustic, mechanical , or electrical stimuli modulating neural activity without the need for opsins. For instance,various organic and inorganic photovoltaic materials have been usedto convert visible light into photocurrents for direct stimulation of bi-ological tissues in vivo. Notably, silicon , metal oxides ,and organic electrolytic photocapacitors have demonstratedthe ability to transform ultraviolet (UV) and visible light into electricalstimuli, which have been applied to the retina, heart, and peripheralnerves. However, these methods are primarily restricted to superficialapplications because of the limited penetration depth of visible light.Therefore, there remains a critical unmet need for a method that en-ables immediate, noninvasive, and remote deep brain stimulation inwild-type animals without genetic modification.

In this work, we developed an instant NIR deep brain stimula-tion method using readily accessible hybrid-UCNP and photovol-taic (HUP) materials in living mice, eliminating the need for geneticmodification and the associated waiting period. This combinationwas chosen on the basis of two main considerations. First, the deeptissue penetration of NIR light is captured and converted into bluelight by rare earth–based UCNP. Second, the blue light is then trans-formed into localized electrical stimuli by photovoltaic materials—specifically, WO3-x in this proof-of-concept study—enablingprecise neural activation in nongenetically modified animals. Unlikeoptogenetics, which requires weeks for opsin expression, the photo-voltaic method provides immediate neural activation upon NIR excita-tion postinjection. By combining the strengths of both key components,we demonstrate that hybrid optoelectronic nanoparticles can effi-ciently achieve noninvasive NIR neurostimulation.

Our in vitro patch clamp experiments demonstrated that neu-rons in brain slices responded with action potentials immediatelyafter HUP was applied and NIR stimulation at 980 nm was deliv-ered. For in vivo validation, we successfully stimulated neurons indeep brain regions, including the medial septum (MS) and ventraltegmental area (VTA). Transcranial NIR stimulation of the MS regioninjected with HUP led to notable hippocampal electrophysiologicalresponses, suppressing seizure activity and inducing synchronous elec-trical signals as early as 7 days postinjection. In the VTA, NIR stimu-lation effectively activated dopamine neurons, confirmed by real-timeelectrochemical measurements as early as 7 days postinjection. Be-havioral observations further showed that NIR stimulation in theVTA induced spatial location preference in a Y-maze, providing func-tional evidence of neural modulation. Immunofluorescence histolo-gy also confirmed substantial c-Fos expression in brain regions nearthe injected HUP, indicating effective cellular activation. Our ap-proach represents a major step forward in the development of faster-acting, less invasive, and more versatile neuromodulation techniques,positioning it as an important advancement in the field of noninva-sive neural stimulation.