A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained‐Release Extracellular Vesicles for Spinal Cord Injury Repair
ABSTRACT Spinal cord injury (SCI) induces neuroinflammation predominantly mediated by microglia, thereby establishing a detrimental milieu that impedes neurological recovery. Extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells (UCMSCs) possess considerable therapeutic potential; however, their clinical translation is constrained by insufficient bioactivity, poor targeting specificity, and uncontrolled release kinetics. Here, we present a multidimensional engineering strategy that overcomes these barriers synergistically. Tetramethylpyrazine (TMP)‐pretreated extracellular vesicles (TEVs) are enriched with anti‐inflammatory and pro‐regenerative factors in their cargo, while Angiopep‐2 (Ang2) peptide‐modified TEVs (Ang‐TEVs) confer significantly enhanced microglial targeting. A reactive oxygen species (ROS)‐responsive hyaluronic acid (HA)‐phenylboronic acid (PBA)/polyvinyl alcohol (PVA) hydrogel serves as an intelligent depot for sustained, on‐demand Ang‐TEVs release at the lesion site. This construct, Ang‐TEVs@Gel, demonstrated robust lesion accumulation and selective microglial uptake. It delivered miR‐664a‐3p, which suppressed PIK3CA to attenuate PI3K‐AKT‐mTOR signaling and unleash autophagic flux, reprogramming microglia toward a reparative state that enhanced myelin debris clearance and quelled inflammation. Consequently, axonal regeneration and remyelination were markedly improved, driving significant motor recovery in SCI mice. By integrating preconditioning, active targeting, and stimuli‐responsive biomaterials, this strategy provides an elegant blueprint for engineering EV‐based therapies to repair the injured central nervous system.