Nanomaterial-genetics enables near-infrared-driven genetically targeted neuromodulation

Stimuli-responsive nanomaterials offer powerful capabilities for neuromodulation, yet there is a continuous need for more versatile methods to ensure cell-specific targeting, a prerequisite for their precise application in neuroscience. To address this gap, we introduce the nanomaterial-genetics (NMG) system, a strategy that integrates genetically encoded synthetic receptors with ligand-functionalized nanoparticles to achieve receptor-guided, cell-selective targeting. Neurons are engineered to express an NMG Receptor carrying an extracellular HaloTag, which selectively captures HaloTag ligand-functionalized gold nanoparticles (AuNP-Ligands). This genetically encoded receptor-ligand pairing enables efficient and localized nanomaterial-mediated photothermal activation under near-infrared (NIR) irradiation at ultralow nanoparticle doses, whereas receptor-negative neurons remain largely unresponsive. Receptor-guided targeting substantially reduces nanomaterial-associated cytotoxicity under the tested conditions while preserving robust neuromodulatory efficacy. We demonstrate genetically targeted activation of neurons in vitro and in vivo, including transcranial NIR modulation of mouse locomotor behavior. Collectively, the NMG system offers an extensible complement to current neuromodulation technologies, providing a versatile platform for multimodal and precision neuromodulation.