CHEMICAL SCIENCE

Valence-engineered self-cascading antioxidant nanoenzymes for the treatment of inflammatory bowel disease


Recently, researchers from the School of Modern Engineering and Applied Sciences of Nanjing University held a research report at Angw. Chem. Int. Ed. published an article titled “A Valence-Engineered Self-Cascading Antioxidant Nanozyme for the Therapy of Inflammatory Bowel Disease.”

In this study, the authors used the spinel oxide ZnMn2O4 (where Zn occupies the tetrahedral position and Mn occupies the octahedral position) as a model to explore the effect of mn at octahedral sites on the various antioxidant activities of nanoenzymes through valence engineering strategies. The first author of the paper is Doctoral Student Wang Quan, and the corresponding author is Professor Wei Hui.

Reactive oxygen species (ROS) are involved in many biological phenomena and play an important role in regulating various physiological functions of organisms. However, excessive production of ROS can trigger oxidative stress in the organism and lead to the occurrence of disease. Reactive oxygen species produced in living organisms can be cleared by natural enzymes with antioxidant functions, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Nanoenzymes are promising enzyme substitutes, but nanoenzymes with a single class of enzyme activity are not enough to effectively remove excess reactive oxygen species in complex pathological environments. At present, multiple antioxidant nanoenzymes lack design strategies, resulting in the inability to achieve optimal multi-variety enzyme activities for most nanoenzymes at the same time (negative correlation). Therefore, it is crucial to study more effective strategies and design nanoenzymes with multiple antioxidant activities at the same time.

Figure 1: A valence engineering strategy for manganese spinel oxides designed for the treatment of IBD with self-cascading antioxidant nanoenzymes.

Multiple oxidation activity determination of ZM, Li-2, Li-4, Li-6 and LM

Scavengering of superoxide radicals is the initial step in an antioxidant cascade. With the addition of Li, the SOD-like activity of the nanoenzyme gradually increased (Figure 2a), and the SOD-like activity of LiMn2O4 (abbreviated as ZM) nearly doubled compared to ZnMn2O4 (abbreviated as ZM). Hydrogen peroxide decomposition is the second step in the antioxidant cascade. Similar trends in CAT-like and GPx-like activities of nanoenzymes (Figures 2b and 2c). The initial model material ZM and low-doped sample Li-2 showed almost no CAT-like and GPx-like activity (test result was negative). When lithium is doped in sufficient amounts, nanoenzymes (especially LM) exhibit significant CAT-like and GPx-like activity. These results show that lithium-doped strategies are an effective way to regulate multiple nanoenzyme activities simultaneously. In addition, the authors also explored the ability of nanoenzymes to scavenge superoxide radicals, hydrogen peroxide and hydroxyl radicals through electron paramagnetic resonance (EPR) experiments. The final optimized material LM all exhibits clear activity and advantages. Based on the above studies of SOD, CAT and GPx activities, the optimized material LM achieves self-cascading antioxidant activity, while the original material ZM has only a single antioxidant activity (Figure 2f).

Figure 2: Antioxidant activities of ZM, Li-2, Li-4, Li-6, and LM. (a) class SOD, (b) cat and (c) class GPx activities of ZM, Li-2, Li-4, Li-6, and LM; (d) • EPR profiles of O2- and (e) H2O2; and (f) comparison of antioxidant activity before and after regulation.

A variety of antioxidant activities regulated by valence engineering strategies

To reveal key factors in the various antioxidant activities of nanoenzymes, the authors measured the material’s X-ray photoelectron spectroscopy (XPS) to study the surface properties of the nanoenzymes. As the amount of Li doped increases, the peak displacement of Mn2p (2p1/2 and 2p3/2) shifts towards the high-energy zone, which indicates a decrease in covalentity (Figure 3a). The results of the fitted peaks showed that the content of Mn4+ (red line) and Mn3+ (blue line) changed significantly. The molar ratio of Mn4+/Mn3+ increased from 0.56 of the initial ZM to 2.29 of the final LM. Thus, mn’s mean valence state increased from 3.36 of ZM to 3.70 of LM (Figure 3b). The relationship between various antioxidant activities and Mn4+ content was plotted, which showed a significant positive correlation. When the content of Mn4+ is increased, all the antioxidant activity of the material is enhanced (Figure 3c).

Figure 3: Antioxidant nanoenzymes based on manganese valence state optimization. (a) Mn2p of ZM, Li-2, Li-4, Li-6 and LM, with red and blue lines representing the fitted peaks of Mn4+ and Mn3+, respectively;

Anti-inflammatory treatment in vivo

Prior to in vivo experiments, the authors also conducted in vitro cell experiments. The results showed that both LM and ZM had good biocompatibility. Compared with ZM, LM exhibited better ability to scavenge intracellular ROS, and further specific probes revealed the ability of LM to regulate intracellular superoxide radicals, hydroxyl radicals, and hydrogen peroxide, respectively.

Based on the excellent antioxidant activity and good biocompatibility of LM, the ability to treat inflammatory diseases was studied in a mouse model of DSS-induced inflammatory bowel disease (IBD). Comparing ZM with the commonly used drug 5-aminosalicylic acid (5-ASA) for the treatment of IBD, Figure 4a summarizes the entire experimental process. A holistic analysis of colon length, weight change, slices, and levels of inflammatory factors revealed the following conclusions: (1) LM, ZM, and 5-ASA all exhibited some degree of therapeutic efficacy; (2) ZM and 5-ASA were similar in therapeutic outcomes; and (3) LM exhibited the most superior therapeutic effect and demonstrated dose advantage.

Figure 4: IBD treatment, tissue sectioning, and cytokine analysis. (a) The overall course of animal experiments; (b) daily weight gain over 11 days; (c) colon images; (d) changes in mouse body weight before and after treatment (day 7) and after treatment (day 10); (e) statistics on colon length; (f) levels of pro-inflammatory factor TNF-α and (g) anti-inflammatory factor IL-10 by experimental group.

summary

Through the valence engineering regulation strategy, the authors show a rare case of simultaneous regulation of multiple antioxidant activities of nanoenzymes. For the model material ZM, with the addition of Li, the SOD-like, CAT and GPx activities of nanoenzymes increased simultaneously. This is the first example of a positive correlation between multiple antioxidant enzyme activities. In addition, the authors revealed the effect of mn valence states at octahedral sites on the multiple antioxidant activities of nanoenzymes. As the ultimate optimized nanoenzyme, LM exhibited the best performance in SOD-like, CAT, and GPx activities, and was validated in cell and animal experiments. This work not only has guiding implications for the development of nanoenzymes with multiple antioxidant activities, but also demonstrates that increased activity and self-cascading design can reduce the dose of therapeutic nanoenzymes, which will broaden the potential of nanoenzymes in biomedical applications. (Source: Science Network)

Related paper information:https://doi.org/10.1002/anie.202201101



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