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

Abstract 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.