| Summary: | Abstract High levels of reactive oxygen species (ROS) and inflammation create a complicated extrinsic neural environment that dominates the initial post‐injury period after spinal cord injury (SCI). The compensatory pathways between ROS and inflammation limited the efficacy of modulating the above single treatment regimen after SCI. Here, novel “nanoflower” Mn3O4 integrated with “pollen” IRF‐5SiRNA was designed as a combination antioxidant and anti‐inflammatory treatment after SCI. The “nanoflower” and “pollen” structure was encapsulated with a neutrophil membrane for protective and targeted delivery. Furthermore, valence‐engineered nanozyme Mn3O4 imitated the cascade response of antioxidant enzymes with a higher substrate affinity compared to natural antioxidant enzymes. Nanozymes effectively catalyzed ROS to generate O2, which is advantageous for reducing oxidative stress and promoting angiogenesis. The screened “pollen” IRF‐5SiRNA could reverse the inflammatory phenotype by reducing interferon regulatory factors‐5 (IRF‐5) expression (protein level: 73.08% and mRNA level: 63.10%). The decreased expression of pro‐inflammatory factors reduced the infiltration of inflammatory cells, resulting in less neural scarring. In SCI rats, multifunctional nanozymes enhanced the proliferation of various neuronal subtypes (motor neurons, interneurons, and sensory neurons) and the recovery of locomotor function, demonstrating that the remodeling of the extrinsic neural environment is a promising strategy to facilitate nerve regeneration.
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