Metal Ion Nanodepots Orchestrate Neuronal Axon and Dendrite Growth via the Actin–PFN1 Pathway

Neurodevelopment is a highly coordinated process involving cell differentiation, neurite extension, axon guidance, and dendritic formation, forming the structural basis for cognitive function. Metal ions such as silver and zinc play essential roles in neuronal disease; however, their precise function in neurodevelopment remains elusive. Due to the solubility characteristics of metal ions and the presence of ion channels on the cell membrane, studying the effects of metal ions within cells presents certain challenges. Recent advances in nanotechnology have enabled the effective delivery of goods into cells in a receptor-independent manner. In this study, we developed 11 types of metal ion nanodepots, NanoMIs, a novel class of nanoparticle-based metal ion delivery systems capable of effective intracellular metal ion release and lysosomal escape. These NanoMIs were applied to primary neuronal cells to investigate their effects on neuronal morphology. Our results show that NanoMIs primarily enhance axon elongation by modulating the PFN1-actin-cytoskeleton pathway. These findings suggest that NanoMIs offer a promising approach for exploring the role of metal ions in neuronal development and provide insights into the molecular mechanisms underlying metal-ion-mediated effects in neuronal cells.