Zinc Hexacyanoferrate Nanoenzymes Attenuate Neuroinflammation After Spinal Cord Injury by Modulating Mitochondrial Function and Microglial Polarization.

Background: Secondary pathology after acute spinal cord injury (SCI) is driven by pathological iron accumulation, reactive oxygen species (ROS) overproduction, and mitochondrial failure, which together sustain chronic neuroinflammation. Methylprednisolone (MP), the most widely used ROS-scavenging agent for acute SCI, provides limited clinical benefit and carries considerable side effects. To address this, we engineered zinc hexacyanoferrate nanoenzymes (ZnHPB) that chelate excess ferrous ions while displaying intrinsic SOD- and CAT-like activities, attenuating oxidative injury at its source rather than merely suppressing downstream inflammation. The defining feature of ZnHPB is a Fe(II)-driven self-reinforcing antioxidant loop in which captured ferrous species are converted into mixed-valence Prussian-blue phases, breaking the Fenton cascade that underpins iron- and ROS-driven secondary injury. Methods: ZnHPB was prepared by polyvinylpyrrolidone-directed self-assembly and characterized for physicochemical and enzyme-mimetic properties. In vitro efficacy was evaluated in H Results: In H Conclusion: By integrating ferrous-ion sequestration with ROS elimination and mitochondrial support, ZnHPB interrupts the self-perpetuating loop of oxidative stress and neuroinflammation that characterizes secondary SCI pathology. Under the conditions tested, ZnHPB compared favorably with MP across multiple preclinical readouts, supporting further mechanistic and translational evaluation.