A biomimetic MnO2 nanozyme–extracellular vesicle platform integrates ROS scavenging and epigenetic modulation to inhibit NLRP3 inflammasome activation in spinal cord injury

Oxidative stress–driven neuroinflammation is a major barrier to functional recovery after spinal cord injury (SCI). Although the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome plays a pivotal role in SCI pathology, effective strategies to simultaneously regulate upstream redox imbalance and inflammasome-associated epigenetic activation are lacking. We developed a biomimetic nanosystem consisting of manganese dioxide nanozymes coated with neural stem cell–derived extracellular vesicles (MnO 2 @EVs). MnO 2 @EVs were locally administered in a murine SCI model. Oxidative stress and mitochondrial function were assessed by dihydroethidium staining, adenosine triphosphate (ATP) quantification, and JC-1 assays. Inflammasome activation and epigenetic regulation were analyzed using Western blotting, enzyme-linked immunosorbent assays (ELISA), chromatin immunoprecipitation–qPCR, and siRNA-mediated knockdown. Proteomics, metabolomics, and single-cell RNA sequencing were employed to elucidate global molecular and cellular mechanisms. MnO 2 @EVs efficiently scavenged excess reactive oxygen species (ROS), restored mitochondrial bioenergetics, and significantly suppressed NLRP3 inflammasome activation. Mechanistically, MnO 2 @EVs inhibited EP300-mediated histone H3K27 acetylation enrichment at the Nlrp3 locus, leading to transcriptional repression of inflammasome signaling. Additionally, MnO 2 @EVs activated the Nrf2–glutathione antioxidant pathway and remodeled the immune microenvironment, markedly reducing inflammatory Nlrp3⁺ microglia populations. These molecular effects translated into improved locomotor function in SCI mice. This study demonstrates that a biomimetic nanozyme platform can integrate ROS clearance with epigenetic regulation to achieve precise immunomodulation after SCI, highlighting MnO 2 @EVs as a promising nanobiotechnology-based therapeutic strategy.