AAV-Driven miR-146a Promotes Neurite Outgrowth and Axonal Regeneration in Cortical Neurons

Adult central nervous system (CNS) neurons exhibit limited intrinsic regenerative capacity, contributing to poor recovery after injury. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, yet their therapeutic potential in CNS repair remains incompletely understood. Here, we investigated whether adeno-associated virus (AAV) vector-mediated overexpression of miR-146a enhances neurite and axon regeneration in primary cortical neurons from Wistar rats. We found that AAV.miR-146a significantly increased neurite outgrowth, branching, and long-distance neurite regeneration following scratch injury. Using a microfluidic platform that allows us to selectively lesion axons, we further demonstrated that AAV.miR-146a robustly promotes axonal regrowth. Bioinformatic analyses revealed enrichment of miR-146a target genes involved in transcriptional regulation and synaptic function, with the inflammatory adaptor TRAF6 emerging as a key predicted target. Consistent with these predictions, AAV.miR-146a markedly reduced TRAF6 expression. Together, our results identify miR-146a as a promising therapeutic candidate for enhancing CNS axonal repair and highlight TRAF6 signaling as a potential mechanistic link to its regenerative effects.