A Closed-Loop-Capable Neural Interface Platform for Deep Brain Modulation via Integrated Non-Viral Gene Delivery, NIR Optogenetics, and Electrophysiological Recording

Closed-loop neuromodulation requires precise, stable, and cell-specific control of neural circuits with minimal invasiveness. However, conventional optogenetic systems are hindered by invasive optical fibers, viral-based gene delivery, and disjointed hardware modules. Here, a multifunctional neural interface integrating non-viral delivery of AAV-derived Channelrhodopsin-2 (ChR2) gene plasmid, fiberless intracranial optogenetic stimulation via externally delivered near-infrared (NIR) excitation, and electrophysiological recording into a single implantable device is reported. The core of this interface is a 3D gold inverse opal (AuIO) microelectrode that provides high surface area, promoting both electroporation-mediated gene transfection and neural signal acquisition. ChR2-expressing plasmid DNA is complexed with polyethyleneimine-neurotensin (NT-PEI) as non-viral gene vectors that are immobilized onto designated electrode sites for neuron-targeted localized gene expression. Upconversion nanoparticles (UCNPs) embedded in a gelatin methacryloyl (GelMA) matrix are precisely integrated onto the microscale AuIO surface via aerosol jet printing, enabling localized surface plasmon resonance (LSPR)-enhanced NIR-to-blue light conversion for remote optogenetic activation. In vivo implantation into the hippocampal dentate gyrus (DG) demonstrates successful opsin expression and real-time light-evoked neural activity via single surgical step. This all-in-one platform provides a fiber-free, biocompatible neural interface capable of stable in vivo operation for deep-brain optogenetic engineering, paving the way for precision closed-loop neuromodulation.