Inflammatory Microenvironment‐Responsive Nanomaterials Promote Spinal Cord Injury Repair by Targeting IRF5

Abstract Spinal cord injury (SCI) involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages rather than prohealing M2 macrophages, and oxidative stress. Interferon regulatory factor 5 (IRF5) is a promising therapeutic target in regulation of macrophage reprogramming from the M1 to M2 phenotype. However, knockdown of IRF5 expression mediated by small interfering RNA (siRNA) is limited by instability and poor cellular uptake. In the present study, polyethylenimine‐conjugated, diselenide‐bridged mesoporous silica nanoparticles are tailored to regulate macrophage polarization by controllably delivering siRNA to silence IRF5. The MSN provides reactive oxygen species (ROS)‐responsive degradation and release, while polyethylenimine‐function offers efficient loading of siRNA‐IRF5 and enhanced endosome escape. As a consequence, the intelligent nanomaterial effectively transfects the siRNA‐IRF5 with its remaining high stability and bioactivity, thereby effectively regulating the M1‐to‐M2 macrophage conversion in vitro and in vivo. Importantly, administration of the functional nanomaterial in crush SCI mice suppresses excessive inflammation, enhances neuroprotection, and promotes locomotor restoration. Collectively, the ROS‐responsive nanomedicine provides a gene silencing strategy for regulating macrophage polarization and oxidative balance in SCI repair.