In Situ Magnetoelectric Generation of miRNA Sponges and Wireless Electric Stimulus by Conductive Granular Scaffolds for Nerve Regeneration

Abstract Electronic signaling and microRNA (miRNA) regulation play pivotal roles in determining neuronal cell fate and promoting brain recovery. Despite this, clinical advancements are hindered by the limited availability of tools for spatiotemporal electrical signaling and non‐viral gene modulation in neurons in vivo. In this study, a conductive granular scaffold (cGRAS) that doubles as an antenna and neuronal gene delivery agent for targeted miRNA regulation of nerve repair in traumatic brain injury (TBI) is developed. The inherent features of granular scaffolds reduce the inflammation and glial scarring in TBI by mitigating activated microglia and stellate cells. Upon irradiation with an external alternating magnetic field (AMF), the “electromagnetic messenger” induces electrical stimulation to restore brain function and promotes temporal electroporation. This process, together with mechanotransduction capability of cGRAS, enhances the delivery and formation of miRNA sponges both in vitro and in vivo, thereby reducing the overexpression of miR6263, which is significantly upregulated upon neuronal injury. In the whole brain imaging analysis, suppression of inflammation, angiogenesis around the TBI cavity, and infiltration of newborn neurons in the injured area are observed after in situ magnetoelectric formation of miRNA sponges and wireless electric stimulus, leading to improved brain function and behavioral recovery. Overall, this cGRAS represents a potentially innovative and versatile tool for clinical neuronal regeneration engineering.