Metformin‐Loaded Schwann Cell Exosomes Reprogram Macrophages and Enhance Neurogenesis in Spinal Cord Injury Through PI3K / AKT Activation

Spinal cord injury (SCI) creates a hostile microenvironment characterized by persistent inflammation and glial scarring, which severely limits endogenous neural regeneration. To address these multifactorial barriers, we developed a targeted nanotherapeutic system comprising glutathione‐functionalized Schwann cell‐derived exosomes loaded with metformin (Exos‐GSH@Met). In vitro and in vivo evaluations showed that GSH functionalization enabled the exosomes to effectively cross the blood‐spinal cord barrier and selectively accumulate in macrophages at the injury site. Transcriptomic sequencing identified the PI3K/AKT pathway as a critical target activated by Exos‐GSH@Met. Mechanistically, the treatment reprogrammed macrophages from a pro‐inflammatory M1 phenotype to a reparative M2 phenotype via PI3K/AKT activation. This immunomodulatory shift subsequently orchestrated the differentiation of neural stem cells (NSCs) into functional neurons while suppressing astrocytic differentiation. Crucially, in vivo blockade of the PI3K pathway using the inhibitor LY294002 negated these regenerative effects, confirming the pathway's centrality. Furthermore, Exos‐GSH@Met not only reduced the density of the glial scar but also significantly inhibited the secretion of pro‐inflammatory cytokines (TNF‐α, IL‐1β, and IL‐6) by reactive astrocytes. Functionally, the treatment significantly improved motor recovery, restored electrophysiological conduction, and ameliorated bladder dysfunction in SCI mice. Collectively, these findings establish Exos‐GSH@Met as a dual‐action platform that coordinates immune microenvironment remodeling and neurogenesis through the PI3K/AKT axis, offering a promising strategy for SCI repair.