Work

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

Year: 2026

Type: article

Abstract: 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: -challenged BV2 microglia in parallel with MP. C57BL/6 mice subjected to T8-T9 contusion SCI received ZnHPB (5 mg/kg, i.p.) under preventive or post-injury dosing regimens for 28 days, with a 60-day safety assessment. Outcome measures included cell viability, ROS levels, mitochondrial bioenergetics (ECAR/OCR), microglial phenotypic markers, plasma injury biomarkers, and histopathology of the lesion. Results: -challenged BV2 cells, ZnHPB improved viability more effectively than MP, with associated reductions in intracellular ROS, partial restoration of mitochondrial OXPHOS capacity, and alleviation of ferroptosis-related transcriptional signatures (GPX4, ACSL4, COX2). In SCI mice, ZnHPB preserved 86.71% (preventive) and 74.06% (post-injury) of white matter at the lesion epicenter and restored plasma CK, AST, and LDH toward physiological levels. Microglial phenotypic markers shifted from an M1-associated toward an M2-associated phenotype. No visceral toxicity was observed over 60 days. 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.

Source: International Journal of Nanomedicine

DOI: 10.2147/ijn.s638767

Authors: Ruifang Liu, Yu Luo, Sen Lin

Institutions: Gannan Medical University, Jinzhou Medical University

Language: English

Topic: Spinal Cord Injury Research

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,836