Wireless Electromagnetic Generation of miRNA Sponges and Nerve Stimulation by an Adaptable Electrical Scaffold for...

Bioelectronic transduction and microRNA (miRNA) regulation play crucial roles in shaping neuronal cell fate and supporting brain repair. However, clinical progress remains limited due to the lack of tools to perform spatiotemporal regulation of neuronal electrical activity and nonviral gene regulation in vivo. In this study, an adaptable electronic scaffold (AES) that functions both as an antenna and gene transfection agent was developed for neuron miRNA modulation in traumatic brain injury (TBI). The intrinsic properties of AES alleviate inflammation and glial scarring after TBI by suppressing activated microglia and stellate cells. Under high-frequency magnetic field (HFMF) stimulation, the "wireless messenger" generates localized electrical cues that aid in restoring brain function as well as enhancing neuronal uptake of gene therapeutics via electroporation. In neurons, AES-induced Eddy currents and mechanical forces further promote endosome escape and the formation of miRNA sponges both in vitro and in vivo, thereby reducing the increase in miR-6236 levels after neuronal injury. The synergic effects achieve in situ gene modulation, promotes neurite outgrowth, and enhance angiogenesis within the lesion. In whole-brain diffusion-weighted magnetic resonance imaging (dMRI), the signal bundles reveal improved intercortical and cortical stellate fiber connectivity, and a recovery in motor function. In summary, this wirelessly driven gene regulation platform combines miRNA-targeted therapy with bioelectronic stimulation to achieve precise neuroregenerative intervention.