Antioxidant Cascade Nanoenzyme Antagonize Inflammatory Pain by Modulating MAPK/p‐65 Signaling Pathway

Abstract Chronic pain has attracted wide interest because it is a major obstacle affecting the quality of life. Consequently, safe, efficient, and low‐addictive drugs are highly desirable. Nanoparticles (NPs) with robust anti‐oxidative stress and anti‐inflammatory properties possess therapeutic possibilities for inflammatory pain. Herein, a bioactive zeolitic imidazolate framework (ZIF)‐8‐capped superoxide dismutase (SOD) and Fe 3 O 4 NPs (SOD&Fe 3 O 4 @ZIF‐8, SFZ) is developed to achieve enhanced catalytic, antioxidative activities, and inflammatory environment selectivity, ultimately improving analgesic efficacy. SFZ NPs reduce tert‐butyl hydroperoxide (t‐BOOH)‐induced reactive oxygen species (ROS) overproduction, thereby depressing the oxidative stress and inhibiting the lipopolysaccharide (LPS)‐induced inflammatory response in microglia. After intrathecal injection, SFZ NPs efficiently accumulate at the lumbar enlargement of the spinal cord and significantly relieve complete Freund's adjuvant (CFA)‐induced inflammatory pain in mice. Moreover, the detailed mechanism of inflammatory pain therapy via SFZ NPs is further studied, where SFZ NPs inhibit the activation of the mitogen‐activated protein kinase (MAPK)/p‐65 signaling pathway, leading to reductions in phosphorylated protein levels (p‐65, p‐ERK, p‐JNK, and p‐p38) and inflammatory factors (tumor necrosis factor [TNF]‐α, interleukin [IL]‐6, and IL‐1 β ), thereby preventing microglia and astrocyte activation for acesodyne. This study provides a new cascade nanoenzyme for antioxidant treatments and explores its potential applications as non‐opioid analgesics.