Remote neurostimulation through an endogenous ion channel using a near infrared light-activatable nanoagonist

The development of noninvasive approaches to precisely control neural activity in mammals is highly desirable. Here we utilized the ion channel TRPA1 as a proof of principle, demonstrating remote near-infrared (NIR) activation of endogenous channels in the neural structures of living mice through an engineered nanoagonist. This achievement enables specific neurostimulation in wild-type, non-genetically modified mice. Initially, target-based screening identified flavins as photopharmacological agonists, allowing for the photoactivation of TRPA1 in sensory neurons upon UVA/blue light illumination. Subsequently, upconversion nanoparticles (UCNPs) were customized with an emission spectrum aligned to flavin absorption and conjugated with flavin adenine dinucleotide, creating a nanoagonist capable of NIR activation of TRPA1. Following the intrathecal injection of the nanoagonist, noninvasive NIR stimulation allows precise bidirectional control of nociception in mice through the remote activation of spinal TRPA1. This study demonstrates a noninvasive NIR neurostimulation method with the potential for adaptation to various endogenous ion channels and neural processes by combining photochemical toolboxes with customized UCNPs.

精准调控哺乳动物神经活动的无创方法极具研究价值与应用需求。本研究以离子通道TRPA1（TRPA1）为原理验证模型，通过工程化纳米激动剂，实现了活体小鼠神经结构中内源离子通道的远程近红外（NIR）激活。该成果可在野生型、非基因修饰小鼠中实现特异性神经刺激。
最初，基于靶点的筛选发现黄素类化合物可作为光药理学激动剂，在UVA/蓝光照射下实现感觉神经元内TRPA1的光激活。随后，研究人员将上转换纳米颗粒（UCNPs）定制为发射光谱匹配黄素吸收特性的载体，并偶联黄素腺嘌呤二核苷酸，构建出可通过NIR激活TRPA1的纳米激动剂。
在对小鼠进行鞘内注射该纳米激动剂后，无创近红外刺激可通过远程激活脊髓TRPA1，精准双向调控小鼠的痛觉感受。本研究结合光化学工具库与定制化上转换纳米颗粒，开发出一种无创近红外神经刺激方法，该方法有望适配多种内源离子通道与神经活动过程。