Wounds can be a serious health problem, especially when they become infected. If not properly treated, wounds with chronic infections can progress to sepsis, multi-organ dysfunction, and in severe cases, death. Difficulties in treating infected wounds are exacerbated by multidrug-resistant (MDR) bacteria, which can make traditional treatment options ineffective. Thus, it has been suggested that inherently antimicrobial nano-systems could be useful for treating MDR infections due to the rarity of antimicrobial resistance to these materials. While many of these inherently antimicrobial nanomaterials are cytotoxic at high concentrations, they are ideal for topical treatments, such as antimicrobial creams and adhesive patches. Due to these characteristics, inherently antimicrobial nanomaterials are a promising treatment for combatting wound infections.

Table 1 3 summarizes recent advances in the use of inherently antimicrobial nano-systems for wound healing applications. Wound healing via inherently antimicrobial nanomaterials has long focused on silver nanoparticles due to their well-established antimicrobial properties. Recent works have improved the known antibacterial properties of silver nanoparticles (AgNPs) by incorporation into a hydrogel ^[1][2][147,148]. Another approach to improve the properties of AgNPs is by hybridization with other nanomaterials to synergistically increase the antimicrobial efficacy. For example, both black phosphorous nanosheets doped with AgNP and AgNP-carrying mesoporous silica-coated single-walled carbon nanotubes have shown increased antibacterial properties when compared to AgNPs alone and have promoted wound healing in mice and animal skin models ^[3][4][149,150]. Other studies have combined the inherent antimicrobial properties of AgNPs with phototherapy to develop hybrid nanotherapies, using a wide variety of photothermal and photosensitizing agents ^[2][5][6][7][148,151,152,153]. Furthermore, both photothermal therapy (PTT), which uses near-infrared (NIR) light to induce localized hyperthermia, and photodynamic therapy (PDT), which uses photochemical reactions to generate ROS, have been combined with many different inherently antimicrobial nanomaterials to increase their efficacy.

The photothermal and photodynamic properties of copper sulfide nanomaterials have made them attractive options for inherently antimicrobial hybrid nano-systems since phototherapy can be combined with the release of Cu²⁺ ions ^[8][9][126,154]. Qiao et al. developed dual-functional copper sulfide nanodots (CuS NDs) to address chronic nonhealing wounds associated with diabetes mellitus ^[9][154]. The CuS NDs were shown to kill MDR bacteria through synergistic mechanisms: hyperthermia due to the photothermal properties of CuS NDs, the release of antibacterial Cu²⁺ ions, and ROS generation due to the photodynamic properties of CuS NDs ^[9][154]. Furthermore, the CuS NDs were found to accelerate wound healing in diabetic mice, due to their hypoxia-mimicking capabilities ^[9][154]. Cu²⁺ ions have been shown to increase the expression of hypoxia-induced factors, which promote angiogenesis. Angiogenesis, or the formation of new blood vessels, is a crucial part of wound healing and may be impaired in chronic diabetic wounds ^[10][155]. Thus, due to their combined antimicrobial, photothermal, photodynamic, and angiogenesis-promoting properties, CuS NDs were an effective hybrid nano-system for the treatment of chronic wound infections and the promotion of wound healing.

[166]. Compared with pure MOFs, the UsAuNPs/MOFs showed increased catalytic efficiency in the presence of H₂O₂, which was maintained under a wide range of pH, salinity, and temperature, indicating increased stability of the hybrid nanozyme ^[21][166]. The POD-like activity of this hybrid nano-system was confirmed via the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB), with the TMB oxidation peak used as an indicator of the conversion of H₂O₂ to the hydroxyl radical ^[21][166]. In vitro assays showed that the UsAuNP/MOF hybrids were effective against S. aureus and E. coli ^[21][166]. Furthermore, the POD-like activity of the UsAuNPs/MOFs was shown to shorten wound healing time in BALB/c mice, with a smaller amount of H₂O₂ required than the 100 × 10⁻³ to 1 M normally used for wound disinfection ^[21][166]. The POD-like activity of the UsAuNP/MOF nanozyme, which was effective in killing bacteria, and its biocompatibility made it excellent for wound healing applications.

While the treatment of infected wounds has been an area of major importance for inherently antimicrobial nano-systems, another application of these systems has been in monitoring wound healing through imaging. Different imaging techniques have emerged as a method to monitor infections and their treatment with nano-systems in real time. Previously photoacoustic imaging has been used with Au/Ag hybrid nanoparticles to monitor silver ion release and improve wound healing in methicillin-resistant S. aureus (MRSA)-infected rat models ^[7][153]. More recently, He and colleagues have used gold-silver nanoshells (AuAgNSs) for PTT-assisted antibacterial treatment of wounds and real-time imaging of infected wounds ^[29][174]. The conjugation of 3,3′-diethylthiatricarbocyanine iodide (DTTC), a Raman reporter, to the AuAgNSs allows real-time monitoring of residual bacteria via surface-enhanced Raman scattering (SERS) imaging. SERS imaging using the AuAgNSs-DTTC showed suitable sensitivity, with the ability to detect 600 CFU/mL extended-spectrum β-lactamase (ESBL) E. coli and 300 CFU/mL MRSA ^[29][174]. Furthermore, the SERS imaging of AuAgNSs-DTTC allowed for in vivo tracking of bacteria for up to 8 days ^[29][174]. In addition to their effectiveness in SERS imaging of bacteria both in vitro and in vivo, the AuAgNSs-DTTC also showed effective antibacterial properties in vitro and wound healing applications in vivo. The antibacterial effect of the AuAgNSs-DTTC is due to the synergistic effect of PTT and silver ions release ^[29][174]. However, recent research has focused on treating chronic wounds, photothermal ablation and imaging, and the use of novel materials to generate reactive oxygen species through enzyme-like nanoparticles.

Implant-associated infections can contribute to medical complications, extend hospitalizations, and increase treatment costs. Current antibiotic treatments for implant-associated infections are often ineffective because many of the bacteria that infect the cells around the implant can form biofilms. Biofilms, which contain bacteria adhered to a surface and surrounded by an extracellular matrix, are difficult to combat with traditional antimicrobial drugs because they impede the penetration of the drugs and block host defenses. This action of biofilms can lead to antibiotic resistance and chronic infections. While some work has been done on the antimicrobial targeting of biofilms, other research has found success in creating inherently antimicrobial coatings for implants to prevent bacterial adhesion to the surface (Table 2).

The modification of implant surfaces with metallic nanoparticles, such as gold, silver, or copper, is a useful strategy for combatting biofilms due to the inherently antimicrobial properties of these nanomaterials. These nanomaterials have broad-spectrum antibacterial activity, long-term stability, and low risk of causing antibiotic resistance, as well as other properties to support the function of the implant in vivo. For example, electrophoretic deposition of ZnO coatings on stainless steel implants has been shown to be effective in preventing the corrosion of the implant material and the preventing growth of S. aureus and S. enteric ^[30][175]. Titanium joint implants coated with AgNPs have been shown to support similar bone formation in uninfected rat tibias over the course of 12 weeks compared to uncoated implants ^[31][176]. In addition, the silver ions released by these AgNPs formed less toxic Ag₂S, which was accumulated mostly in the osseous tissue directly surrounding the implant surface ^[31][176]. Tissue engineering has also been accomplished with nonmetal materials, such as silk fibroin scaffolds containing AgNPs, which have been shown to support the differentiation of human mesenchymal stem cells and to be effective against Gram-negative bacteria and antibiotic-resistant bacteria ^[32][177]. Recently, inherently antimicrobial nano-systems have been used to modify bone implants, stents, and catheters in order to prevent implant-associated infections.

The photothermal properties of molybdenum sulfate nanoparticles have also generated interest in their use as hybrid nano-systems with inherently antimicrobial properties ^[18][19][20][163,164,165]. In one prominent study, MoS₂ nanoflowers functionalized with polyethylene glycol (PEG-MoS₂ NFs) were used to catalyze the decomposition of H₂O₂ to the hydroxyl radical to kill bacteria ^[19][164]. This peroxidase (POD)-like activity was combined with PTT to increase the antibacterial efficiency of the nano-system against ampicillin-resistant E. coli and B. subtilis ^[19][164]. Additionally, the hyperthermia caused by PTT increased the rate of glutathione oxidation, which contributed to the antibacterial activity, due to the role that glutathione has in preventing cellular damage due to oxidative stress ^[19][164]. The combined effects of hyperthermia and the catalytic activity of PEG-MoS₂ NFs made them a potent hybrid nano-system for wound healing applications. The ability to behave as a POD-like catalyst has been observed in other nanomaterials, making them appealing candidates for wound healing applications. The POD-like activity of ultra-small gold nanoparticles (UsAuNPs) was investigated by Hu and colleagues for the treatment of infected wounds. The POD-like activity of these nanoparticles not only gave them inherently antimicrobial properties but also enabled the UsAuNPs to act as nanozymes, that is nanoparticles that mimic the reaction mechanisms of naturally occurring enzymes. Due to their ultra-small size, UsAuNPs have high enzymatic activity; however, UsAuNPs are unstable and tend to for aggregates due to their large surface energy. Hybridization with a molecular organic framework (MOF) stabilized the UsAuNPs and improved their catalytic performance ^[21]

The most common treatment for patients with cardiovascular atherosclerosis is stent implantation, which can lead to numerous complications such as blood clotting or delayed endothelialization. Dai et al. ^[36][181] developed an inherently antimicrobial nano-system for use in vascular stents using TiO₂-NTs loaded with AgNPs and pre-treated with UV radiation. While TiO₂-NTs are excellent drug carriers, they have been reported to induce thrombosis, which reduces their biocompatibility. However, it has previously been shown that UV irradiation can improve the anticoagulant activity of TiO₂ films by inhibiting fibrinogen adsorption and platelet adhesion through the generation of ROS ^[59][60][204,205]. Furthermore, TiO₂-NTs can also carry inorganic materials, such as AgNPs, which are more stable during UV irradiation than organic drugs. For these reasons, Dai et al. tested UV-treated TiO₂-NTs loaded with AgNPs (UV-NTs@AgNPs) as a potential material for stents ^[36][181]. UV-NTs@AgNPs exhibited anticoagulant properties and selective inhibition of smooth muscle cells and macrophages in vitro ^[36][181]. When implanted in the abdominal aorta of Sprague Dawley rats, UV-NTs@AgNPs had decreased thickness of tissue formed on the surface of the nano-system when compared to the untreated TiO₂-NTs@AgNPs, showing greater histocompatibility. Additionally, tissue around the implants showed more inflammation in the non-irradiated TiO₂-NTs@AgNPs, and the UV-NTs@AgNPs had lower intimal hyperplasia thickness than the non-irradiated nano-systems ^[36][181]. Furthermore, the UV-NTs@AgNPs showed greater biocompatibility than the non-irradiated TiO₂-NTs@AgNPs. These results indicated that the UV-NTs@AgNPs were a good candidate for vascular stents. The antibacterial properties of AgNPs made them not only useful for stents but also for other implants, such as catheters.

The use of intravenous catheters (IVCs) in patients can often lead to the development of infections. IVC-related infections are most commonly caused by Staphylococcus bacteria, including MRSA. While using aseptic techniques for inserting the catheter can reduce IVC-related infections, it does not completely prevent IVC-associated infections and is insufficient to prevent infections caused by antimicrobial-resistant organisms, such as MRSA. Due to their effectiveness against a broad spectrum of microorganisms, silver and copper nanoparticles are a natural choice for the coating of polyurethane catheters. Ballo and colleagues used direct current magnetron sputtering to coat polyurethane catheters with a 67% AgNPs 33% copper NPs mixture and tested their effectiveness against MRSA both in vitro and in vivo ^[44][189]. While the Ag/Cu coating was effective in vitro, preventing 80% of catheter colonization by MRSA, the catheter coating was less effective in vivo ^[44][189]. When inserted into the jugular vein of female Wistar rats, the Ag/Cu-coated catheters only prevented 22% of infections ^[44][189]. However, the Ag/Cu-coated catheters did show a decrease in bacteremia compared to uncoated catheters. The adhesion of plasma proteins and the formation of a fibrin sheath on the surface of the catheter likely inhibited the antimicrobial activity of the Ag/Cu-coated catheters in vivo, which probably contributed to their poorer performance ^[44][189]. While the Ag/Cu-coated catheters did not perform as well in vivo as they did in vitro, further studies could improve the nano-system by preventing the formation of the fibrin sheath or the deposition of plasma proteins.