Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington’s Like Disorder in Preclinical Model

Abstract

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, we have shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn3O4 NP) efficiently mimics glutathione peroxidase enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. We further established the in vivo therapeutic efficacy of C-Mn3O4 nanozyme in a preclinical animal model of Huntington’s disease, a prevalent progressive neurodegenerative disorder, which has no effective medication till date.SUMMARYAlthough, nano-enzymes have shown lots of promises in the management of several diseases, two major concerns limit their clinical translation. Apart from the inherent toxicity of the constituent materials (e.g., cerium, vanadium, gold, etc.), activities of contemporary nanozymes are often inhibited in physiological milieu. Furthermore, most of them are incapable of incorporation into the cellular metabolic networks for functioning in tandem and parallel with natural enzymes, a major criteria for potential therapeutics.Here, we have shown that citrate-functionalized spherical Mn3O4 nanoparticles can efficiently mimic glutathione peroxidase (GPX) enzyme without the limitations of contemporary nanozymes, and effectively manage neurodegenerative Huntington’s disease in preclinical animal model. The choice of the material in the nanozyme lies on the fact that Mn is an essential micronutrient for mammals, and the stabilizing ligand citrate helps the nanoparticles to cross the blood-brain-barrier to reach brain. We have shown that the nanozyme can easily be incorporated in cellular antioxidant enzyme cascade. The specificity and efficacy of the nanozyme in the cascade was significantly higher compared to other reported nanozymes. We have justified our experimental findings with a detailed computational study. Understanding the mode of operation and management of Huntington’s disease in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.

Redox Buffering Capacity of Nanomaterials as an Index of ROS-based Therapeutics and Toxicity: A Preclinical Animal Study

“…It has to be noted that the redox buffering capacity of the C-Mn 3 O 4 NPs in cellular system is considerably higher compared to in vitro aqueous system. This may be due to the additional (i.e., other than direct antioxidant activity) GPx mimicking activity of the C-Mn 3 O 4 NPs [18] which can only happen in presence of GSH, and intracellular metabolite.…”

Structure design mechanisms and inflammatory disease applications of nanozymes

“…94 Furthermore, Adhikari et al proved that the Mn 2+ is the catalytic center of GPx-like activities using DFT calculation. 71 They proved the mechanism of the GPx-like reaction on the Mn 2+ catalytic center and computed the Gibbs free energy (ΔG = −6.3 kcal mol −1 ). Thus, the adsorbed H 2 O 2 will spontaneously split on the Mn 2+ center, forming a peroxide species (Fig.…”

“…Most of them possess multiple enzyme-like activities. Taking advantage of their excellent enzyme-like properties, Mn-based nanozymes are widely used in the treatment of inflammatory diseases, [68][69][70] neurodegenerative diseases, 71 and cancer, 72,73 and in the field of in vitro detection. [74][75][76][77] Besides, Mn-based nanozymes are used as contrast agents in MRI because Mn 2+ is paramagnetic in nature.…”

“…Scientists use these nanozymes to treat ROS-related diseases such as cerebral ischemic stroke, Parkinson's disease, Huntington's disease, and so on. 5,68,71,92 Generally speaking, the enzyme-like activity is closely related to the particle size, specific surface area, morphology, and surface valence of the material. For metal oxide, increasing the oxygen vacancy concentration on the surface is also a means to improve the enzyme activity of the material.…”

A Valence‐Engineered Self‐Cascading Antioxidant Nanozyme for the Therapy of Inflammatory Bowel Disease

“…[7] To this end, such a nanozyme can achieve more significant therapeutic efficacy in the treatment of diseases and may even reduce the administration dosage. Because of the above-mentioned limitations of available nanozymes with multiple antioxidant activities, the current cascade nanozymes are mainly constructed by two or more materials, [8] which require delicate material design and complicated material synthesis. These requirements can be satisfied by developing self-cascading antioxidant nanozymes with simultaneous multi-activities.…”