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 Fe3O4 NPs (SOD&Fe3O4@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‐1β), 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.

Analgesic nanomedicines for the treatment of chronic pain

“…Reproduced with permission. [24] Copyright 2023 Wiley-VCH. CFA, complete Freund's adjuvant; SFZ, SOD&Fe 3 O 4 @ZIF-8.…”

“…Artificial nanozymes with enzyme‐like catalytic activity are gradually becoming an alternative due to their long‐term stability, high tolerance, and catalytic versatility. For instance, Ling et al., [24] developed an antioxidant cascade nanozyme, SOD&Fe 3 O 4 @ZIF‐8 (SFZ), by encapsulating superoxide dismutase (SOD) and Fe 3 O 4 in Zeolitic Imidazolate Framework‐8 (ZIF‐8) for the treatment of inflammatory pain (Figure 4a,b). SOD is a primary antioxidant enzyme in the body that can catalyze the conversion of superoxide anion radicals into hydrogen peroxide and oxygen, thus reducing oxidative stress.…”

“…(c) Mechanical allodynia of CFA‐induced mice treated with different concentration gradients of SFZ NPs. Reproduced with permission [24] . Copyright 2023 Wiley‐VCH.…”

Trifunctional Nanocomposites with Colorimetric Magnetic Catalytic Activities Labels in Sandwich Immunochromatographic Detection of Escherichia coli O157:H7

“…Fortunately, the emergence of nanoenzymes has led to a flourishing development of LFIA. In nanoenzyme-based LFIA, nanoenzymes are not only used as signal generators and targets but also play a key role in sensor sensitivity and anti-interference performance through their catalytic and colorimetric abilities. − Among numerous nanozymes reported so far (including noble metals, , metal oxides, − metal–organic frameworks, − and bimetallic nanostructures − ), metal oxide nanozymes have appeared as the most efficient and promising candidates to apply in LFIA. Furthermore, plenty of methods have been developed to modulate the biosensor performance, but the current effectiveness is unsatisfactory due to the insufficient catalytic properties and poor stability of antibody loading.…”

JNK signaling mediates acute rejection via activating autophagy of CD8+ T cells after liver transplantation in rats

“…JNK1 and JNK2 subtypes are widely expressed in various tissues and organs, while JNK3 is expressed mainly in the brain and nerves ( 10 ). The JNK pathway is activated in response to a variety of stimuli, such as oxidative stress, inflammation, DNA damage, and cytoskeleton remodeling ( 11 – 13 ). JNK pathways are reported to promote the expression of various autophagy related genes including Atg5, Atg7 and Beclin-1 directly or through FoxOs, thereby activating autophagy ( 14 ).…”