Targeting Microglia Extracellular Traps via an “Internal‐External” Synergistic Strategy to Reshape the Dysregulated Microglia‐Neuron Axis for Spinal Cord Injury Recovery

Abstract Macrophage extracellular traps (METs) are highly correlated with the inflammatory response following central nervous system (CNS) injury. However, how to effectively target and inhibit the formation of METs remains a significant challenge. This study investigated the development of a tailored “combination of internal and external” strategy through the design of multifunctional nanozymes (DNase I@CeO 2 /Man) to inhibit and degrade METs after spinal cord injury (SCI). The DNase I@CeO 2 /Man construct consisted of hollow cerium dioxide (CeO 2 ) nanoparticles decorated with mannan (Man) and loaded with deoxyribonuclease I (DNase I). The presence of Man on the surface of the nanomedicine facilitated selective internalization by microglia rather than neurons. Hollow CeO 2 nanoparticles loaded with DNase I exhibited strong reactive oxygen species (ROS) scavenging capabilities and enabled the sustained release of DNase I, thereby effectively inhibiting the formation and promoting the degradation of METs. Furthermore, DNase I@CeO 2 /Man preserved mitochondrial homeostasis to reduce the leakage of mitochondrial DNA (mtDNA) and inhibited the cGAS/Sting signaling pathway, thereby mitigating the formation of METs from inside microglia. The released DNase I efficiently eliminated METs from the external environment of microglia. Moreover, DNase I@CeO 2 /Man is capable of modulating the anti‐inflammatory phenotypic transformation of microglia, suppressing inflammatory cascades, and subsequently restructuring the microglia‐neuronal cell axis by regulating the c‐Caspase 1‐GSDMD‐IL‐1β/IL‐18 pathway to prevent neuronal pyroptosis. In a murine model of SCI, the administration of DNase I@CeO 2 /Man significantly enhanced motor function and promoted axonal regeneration. In summary, this study not only presents a novel approach for inhibiting METs but also establishes a new framework for the treatment of other CNS injury‐related disorders.