Targeted Biohybrid Nanoplatform for Spinal Cord Injury Treatment: Restoring Microglial Mitophagy and Alleviating Oxidative Stress

Spinal cord injury (SCI) remains refractory because oxidative stress, impaired mitochondrial quality control, and maladaptive microglial activation form an interdependent cascade that sustains secondary degeneration. Here, we develop a modular biomimetic nanozyme platform (PM-Lipo@PB NPs) by integrating distinct functional components into a unified system. Platelet-derived membrane vesicles (PMVs) and M2 macrophage–derived extracellular vesicles (M2EVs) are fused to form a hybrid membrane (PM-Lipo) that mediates lesion-associated accumulation and provides immunoregulatory cues, while a Prussian blue (PB) nanozyme shell is grown in situ to confer catalytic redox activity. This design enables concurrent vascular injury–associated enrichment, interaction with activated microglia, and localized ROS scavenging within the lesion microenvironment. PM-Lipo@PB NPs accumulate at the injury site and reduce oxidative burden, thereby contributing to the recovery of mitochondrial function and cellular homeostasis. These effects are accompanied by modulation of PI3K/AKT/mTOR signaling and restoration of mitophagic flux, together with a shift of microglia toward a reparative phenotype. In cellular and murine SCI models, the platform exhibits lesion-preferential accumulation, effective ROS clearance, reduced inflammatory activation, and improved tissue preservation and motor function. Taken together, this study establishes a modular strategy that couples membrane-derived biological functionality with nanozyme-based redox regulation, providing a basis for microenvironment-directed therapy in SCI and related neuroinflammatory conditions. • Key Highlights • Biohybrid membrane engineering: Fused platelet–M2EV hybrid membrane enables synergistic vascular targeting and inflammatory homing. • Catalytic mitochondrial rescue: PB nanozyme clears ROS and suppresses PI3K/AKT/mTOR to restore mitophagic flux. • Microglial reprogramming: Promotes anti-inflammatory transition and resolves chronic neuroinflammation. • Microenvironment reconstruction: Enhances angiogenesis and preserves neuronal integrity after SCI. • In vivo efficacy: Achieves significant neuroprotection and functional recovery. • Modular platform: Adaptable for CNS injuries involving oxidative and mitochondrial dysfunction.