An NIR-II-Enhanced Nanozyme to Promote Wound Healing in Methicillin-resistant Staphylococcus Aureus Infections

Infectious bacteria pose a major challenge to human health, for which antibiotic therapy remains the most common clinical treatment [1]. Staphylococcus aureus, a type of infectious bacteria, can exist harmlessly in organisms and will not cause skin infections. However, when it enters the circulatory system of the human body, S. aureus can lead to serious diseases [2]. Unfortunately, due to the overuse of antibiotics not only can they be toxic to the normal tissues of the body also contributes to the emergence of methicillin-resistant Staphylococcus aureus (MRSA). MRSA has become almost ubiquitous, posing a significant challenge to effective treatment and infection control in medical facilities [3,4].

With the continuous development of modern technology, inorganic nanomaterials exhibit unique physicochemical properties due to their size with stability and low toxicity making them suitable for application in antimicrobial therapy [5], [6], [7], [8]. Among them, nanozymes with tunable, long-term storage, good stability and tunable catalytic properties have been widely used in the fields of biosensing, disease treatment, pollutant degradation and antimicrobial therapy [9,10]. Nanozymes can generate reactive oxygen species (ROS), which include hydroxyl radicals, hydrogen peroxide, and single-linear oxygen species, through one-electron reduction reactions [11]. To date, significant progress has been made in the use of Nanozymes as a new generation of "antibiotics" for chemodynamic therapy (CDT) to inhibit bacterial infections [12]. Broad-spectrum nanozymatic "antibacterial agents" such as Au/g-C3N4 hybrids, Cu2WS4 nanocrystals, silver-ion-implanted porphyrin MOFs, and copper/carbon hybrids such as Cu2WS4 nanozymes have oxidase-like and peroxidase-like properties. Peroxidase-like enzymes have been widely studied for their ability to convert low concentrations of H2O2 into hydroxyl radicals to disrupt biofilms and kill bacteria [13,14]. However, high concentrations of H2O2 impede the recovery of wound tissue, thus limiting the bactericidal activity of peroxidases alone [15]. Therefore, it can be used to construct a series of antimicrobial systems based on peroxidase-like properties [16], [17], [18]. Based on the fact that excitation of near-infrared light sources has been recognized as a catalytic behavior that can modulate enzyme-like activity. In recent years, photothermal therapy (PTT) is an innovative antimicrobial method that is gaining popularity in the antimicrobial field due to its significant advantages such as selectivity and efficacy [19], [20], [21], [22], [23], which destroys bacteria through the use of near-infrared (NIR) light-induced warming of photothermal agents (PTAs) [24], [25], [26]. The common materials used as PTAs are mainly Au nanomaterials, Pt nanoparticles, and CuS nanosheets. Narrow bandgap semiconductor materials can also produce significant photothermal effects, mainly including Ti2O3 nanoparticles, black TiO2, MoO3 quantum dots, and metal oxide semiconductors such as Fe3O4. However, photothermal treatment of bacterial infections requires a temperature threshold of ≥70°C [27], and strong lasers (localized temperatures of 50°C or more) are often accompanied by the risk of burns to normal skin tissues [28]; therefore, combining other antimicrobial technologies and selecting an appropriate PTT treatment temperature are key issues in achieving effective photothermal therapy. This study utilized combined photothermal/chemodynamic therapy. The combined action of PTT and CDT has great potential to overcome their respective drawbacks. This gives the MoWS2 material an even greater advantage in terms of antimicrobial efficacy.

Two-dimensional transition metal disulfide nanosheets (2D TMDC NSs) such as graphene and other new inorganic analogs have received much attention in recent years. These materials display unique and promising properties that make them attractive for a variety of applications in fields such as photovoltaics, materials science, biomedicine, energy, and catalysis [29], [30], [31], [32], [33]. These materials generally consist of a layer of transition metal atoms sandwiched between two layers of sulfur atoms, and include MoS2, WS2, TiS2, MoSe2, WSe2, and other similar compounds. MoS2 nanosheets are considered to be highly reliable and efficient PTAs due to their good biocompatibility and photothermal effect in the near-infrared I (650-900 nm) window [34], [35], [36], [37], [38], [39], [40]. In recent years, reports of molybdenum disulfide and its related nanomaterials such as MoS2-bPEI-CeFe2O4 and E-MoS2 are mostly used as PTAs in the NIR-I window for PTT therapy [41,42]. However, these therapies are still limited in clinical application to some extent due to the poor penetration and depth of NIR light [43]. Moreover, most of the developed 1T-MoS2 PPT therapies or antimicrobial systems based on PTT therapies constructed with MoS2-associated nanomaterials are sterilized in vivo at a temperature of 55°C or higher [36,38,44,45], which has the risk of damaging normal tissues of the skin [46,47]. We prepared MoWS2 can use the near infrared two-region (NIR-II) window technology can be an effective solution to such problems, near infrared-II band (1000-1350 nm) light and near infrared-I band light compared to the NIR-II window photons interact with the tissues to reduce the depth of penetration is much stronger, we will be the experimental temperature control at the highest temperature of 50°C or so, to increase the activity of peroxidase and at the same time, the effect on the skin. We control the maximum temperature of the experiment around 50°C to increase the peroxidase-like activity without harming the normal skin. To a more effective, gentler and deeper antibacterial strategy is realized.

In this study, the nanozymatic material MoWS2 is produced, which is a member of the transition metal dichalcogenides (TMDCs) group. TMDCs exhibit a diverse elemental composition and electronic structure, including conductive materials such as superconductors and charge density wave materials, as well as semiconductors [48], [49], [50]. Most TMDCs are bound within layers by strong covalent/ionic bonds but are loosely held between layers by weak van der Waals forces. This interlayer weakness facilitates their facile exfoliation into single or few layers. We synthesized the nano-enzymatic material MoWS2 by hydrothermal method to make W atoms replace some of the Mo atoms. The atomic radius of tungsten is much larger than that of molybdenum, and the doping of W produces a large number of defects and lattice distortions thus modulating the properties [51]. Finally, the material reacts with N2H42+ under hydrothermal conditions and swells by redox rearrangement. The swollen material reacts with an alkaline solution and peels off multilayered sheets in water. The synthesized tungsten-doped molybdenum disulfide (MoWS2) significantly improved the photothermal performance and efficiency (36.9%) compared to 2H-MoS2. This remarkable improvement in photothermal performance enhances the effectiveness of chemical kinetics, and synergistically enhances bactericidal capacity (Scheme 1). In general, this study demonstrates the influence of MoWS2 on the activity of methicillin-resistant S. aureus and its impact on wound healing in animal models. In addition, it provides an experimental basis for the development of systemic treatment of methicillin-resistant S. aureus infections using MoWS2 nanozymes in combination with PTT in clinical settings.

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