Magnetic Nanoparticle‐Mediated PTEN Inhibition Promotes Directional Neurite Growth for Spinal Cord Injury Repair

ABSTRACT Adult mammalian spinal cords have limited regenerative capacity, and spinal cord injury (SCI) often causes permanent neurological deficits. Although genetic interventions may enhance intrinsic growth capacity in injured neurons, axonal extension after SCI may remain spatially limited and poorly organized, which may restrict functional recovery. Here, we developed dual‐function magnetic nanoparticles to integrate intrinsic neurite growth activation with external magnetic guidance for directional neurite elongation and functional recovery after SCI. Superparamagnetic iron oxide nanoparticle (SPION)‐embedded poly(lactic‐co‐glycolic acid) (PLGA) cores were sequentially coated with reactive oxygen species (ROS)‐responsive poly[(2‐acryloyl)ethyl(p‐boronic acid benzyl)diethylammonium bromide] (bPDEA), phosphatase and tensin homolog (PTEN)‐targeting small interfering RNA (siPTEN), and an outer bPDEA layer. The bPDEA layer promoted cellular internalization and ROS‐responsive siPTEN release in the oxidative injury microenvironment. PTEN suppression was accompanied by increased protein kinase B (AKT) and glycogen synthase kinase 3β (GSK‐3β) phosphorylation. SPION‐containing nanoparticles conferred magnetic responsiveness, allowing neurite extension to be biased by an external magnetic field. In mice with SCI, this treatment increased enhanced green fluorescent protein (EGFP)‐positive axonal profiles around and caudal to the lesion, reduced glial fibrillary acidic protein (GFAP) and ionized calcium‐binding adapter molecule 1 (Iba1) immunoreactivity, and improved locomotor outcomes. These findings provide proof‐of‐concept for combining PTEN‐targeted growth activation with magnetic‐field‐dependent modulation of neurite growth to improve outcomes after SCI.