Figure 8. (a) Infrared thermal images of two mice injected with either the CuCo2S4 NCs (the right one, indicated region 12) or PBS (the left one, indicated region 11), respectively, irradiated with an 808 nm laser (0.56 W cm−2) for 60 s. (b) Histological analysis of carotid artery stenosis in a mouse model. (c) H&E staining images of the main visceral organs in the Apo E −/− mice treated with the CuCo2S4 NCs after MPTT. Reproduced from Ref. [208] with permission. Copyright 2019 Royal Society of Chemistry.
4.3. Wound healing
Bacterial infection is one of the main causes of human death. Microvascular dysfunction caused by hyperglycemia in diabetic patients leads to slow diabetic wound healing, which significantly increases the risk of bacterial infection in the process of wound healing. At present, antibiotics are the most used drugs to deal with bacterial infections in clinical treatment.[211-213] However, the inappropriate use of antibiotics leads to the emergence of multi-drug resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), which seriously limits the therapeutic effect of antibiotics. Therefore, the development of antibiotic-free antimicrobial agents and strategies is essential for the management of infected wounds in diabetic patients.[214-216] MPTT under the stimulation of NIR light can specifically kill pathogenic bacteria. In addition, MPTT can effectively alleviate the intermolecular forces or reduce the volume, and local temperature changes can also lead to structural changes in the hydrogel network, achieving rapid drug release and reducing the incidence of bacterial infection, thereby accelerating wound healing. As an important biomaterial, hydrogel has attracted much attention in the field of biomedicine due to its good biocompatibility, adjustable degradability, and suitable mechanical properties. Moreover, hydrogels are porous, highly flexible and can hold a specific amount of water up to 90%, and these ”soft and wet” properties provide a living tissue-like environment, thus making them a suitable biomaterial for healthcare.[217-220] Therefore, many researchers have proposed this ”two birds with one stone” strategy: after eliminating diseased cells with PTT, the hydrogel is used for tissue repair, to exert a synergistic therapeutic effect under laser irradiation.
In the study by Xu et al., the researchers aimed to develop a nanocatalytic antibacterial system for promoting wound healing while addressing bacterial infections. The system utilized a combination of MPTT and nanocatalysis, with a focus on rapid bactericidal action and tissue repair. The core of the system consisted of hydroxyapatite (HAp) nanoparticles incorporated with gold NPs (Au-HAp), further coated with a layer of PDA to enhance their functionality. The PDA@Au-HAp NPs were designed to generate hydroxyl radicals (•OH) through catalysis of a small concentration of H2O2. These •OH radicals were effective in rendering bacteria more vulnerable to temperature changes. The antibacterial efficacy of the nanoparticles was demonstrated against Escherichia coli and Staphylococcus aureus, with high bacterial reduction rates of 96.8% and 95.2%, respectively. Importantly, this bactericidal effect occurred at a controlled photo-induced temperature of 45°C, which was shown to cause no damage to normal tissues. The combination of catalysis and MPTT provided a synergistic antibacterial effect that was safe, rapid, and highly effective compared to •OH or MPTT alone. Furthermore, the PDA@Au-HAp stimulated the expression of tissue repair-related genes, facilitating the formation of granulation tissues and collagen synthesis, thereby accelerating the wound healing process.[221] Overall, this research presents a promising nanocatalytic antibacterial system that combines MPTT and nanocatalysis to promote wound healing while effectively addressing bacterial infections. Yuan et al. developed an all-in-one phototherapeutic nanoplatform for the elimination of biofilms, challenging to treat the resistance of antibiotics and other conventional therapies. Biofilms are communities of bacteria that can form on various surfaces, including medical implants, and are associated with chronic infections. The developed nanoplatform, termed AI-MPDA, consisted of several key components: Mesoporous Polydopamine (MPDA) served as the core material for the nanoplatform and provided a stable structure for further modifications. L-Arginine (L-Arg) was performed to introduce a key therapeutic component to produce NO, a molecule with antibacterial properties. ICG was adsorbed onto the MPDA surface via π−π stacking that can generate ROS upon exposure to NIR light. The nanoplatform generated heat upon NIR irradiation, which contributed to the MPTT component of the treatment. Importantly, the treatment temperature was kept relatively low (≤45°C) to minimize damage to surrounding healthy tissues. The combination of these therapeutic actions resulted in the effective elimination of biofilms, including the destruction of bacterial membranes. Importantly, the AI-MPDA nanoplatform demonstrated good compatibility with human cells. In addition to its efficacy in biofilm elimination, NIR-irradiated AI-MPDA were also shown to prevent bacterial colonization and promote rapid wound healing in infected wounds.[222] Overall, this study presented an innovative mild phototherapeutic platform, AI-MPDA, as a reliable tool for combating already-formed biofilms in clinical applications. The platform’s ability to combine PTT, PDT, and NO release makes it a promising approach for addressing biofilm-related infections. Qiang et al. proposed a novel approach for the controlled and gentle killing of bacteria using MPTT. Unlike traditional PTT methods that often lead to bacterial cell necrosis, this approach aimed to induce a mode of bacterial cell death resembling apoptosis, where the bacterial cell membranes remain intact, but the bacteria are unable to proliferate. MPTT did not directly destroy the outer membranes of the bacteria but instead triggered the gradual efflux of calcium ions (Ca2+) and magnesium ions (Mg2+) from the bacterial intracellular content. While the outer membranes remained intact, the treatment caused dynamic variations in the surface micromorphology of the bacterial membranes. The study also demonstrated that the viability of E. colibacteria could be dynamically changed through different temperature ranges. This controlled MPTT strategy was found to be more effective in promoting the healing of wounds in mice when compared to higher PTT temperatures (e.g., 58 °C).[223] This innovative approach offers potential applications in wound disinfection and healing in clinical settings by utilizing a MPTT strategy that selectively targets and controls bacterial growth while preserving the integrity of tissues. It represented a promising direction for the development of more gentle and effective antibacterial therapies. Duan et al demonstrated a novel approach for advanced antibacterial therapy and wound disinfection using a carrier system based on porous silicon (PSi) modified with PDA. This innovative system, referred to as CuPDA-coated PSi microcarrier (CuPPSi), was designed to possess both photothermal and therapeutic capabilities for enhanced antibacterial effects and wound healing. CuPPS allowed for the incorporation of therapeutic components while maintaining the PSi’s mesoporous structure. CuPPSi exhibited a significant photothermal effect when exposed to NIR laser irradiation. This property was attributed to the presence of PDA on the carrier’s surface, enabling efficient conversion of NIR light into heat. CuPPSi demonstrated stimuli-responsive drug release behavior, triggered by factors such as pH, ROS, and NIR laser irradiation. This feature allowed for controlled and targeted release of antibacterial agents, including Cu2+ ions and curcumin (Cur). CuPPSi-Cur platform exhibited a synergistic antibacterial effect, effectively killing over 98% of both Staphylococcus aureus and Escherichia coli bacteria at a MPTT temperature of approximately 45 °C.[224] The study highlighted the potential of the CuPPSi-Cur platform as an intervention for amplifying wound disinfection in clinical settings. By combining the photothermal and therapeutic effects, this innovative approach offers a promising strategy for addressing bacterial infections and promoting wound healing with improved precision and efficacy. In the study conducted by Shi et al., the researchers developed a biomimetic non-antibiotic nanoplatform for the low-temperature photothermal treatment of urinary tract infections (UTIs) caused byuropathogenic Escherichia coli (UPEC). This innovative nanoplatform addressed the challenges associated with antibiotic resistance and the potential tissue damage caused by high local temperatures in traditional PTT. The nanoplatform consisted of two main components: a PDA photothermal core and a biphenyl mannoside (Man) shell. The Man shell was designed with multivalent high-affinity binding to UPEC, ensuring effective targeting. The PDA-Man nanoplatform was designed to deliver high photothermal energy selectively to the bacterial clusters. This allowed for the effective photothermal bactericidal effect within the bacterial area while maintaining a low temperature in the surrounding environment. In UTI models, the fabricated nanoplatform demonstrated excellent photothermal bactericidal effects, achieving approximately 100% bacterial elimination.[225] The MPTT nanoplatform provides a promising strategy for the elimination of bacteria in clinical applications, particularly for the treatment of UTIs caused by UPEC. By avoiding high local temperatures, this approach minimizes the risk of tissue damage while effectively targeting and eliminating bacteria. Overall, this study presented an innovative and clinically relevant approach to combat UTIs, addressing the growing concern of antibiotic resistance and improving the precision and efficacy of bacterial elimination using MPTT. Zhu et al. proposed a novel antibiofilm strategy called Iron-Actuated Janus Ion Therapy (IJIT), which aimed to regulate iron metabolism in both bacterial biofilm and immune cells. This approach involved the use of a biofilm microenvironment (BME)-responsive photothermal microneedle patch (FGO@MN) as a key component. These nanomaterials were encapsulated in methacrylated HA needle tips, which exhibited a photothermal effect. The combination of FGO@MN-induced thermal sensitization and MPTT led to increased iron uptake within bacterial biofilms. This intracellular iron overload subsequently induced a ferroptosis-like form of cell death. The study also demonstrated that iron-nourished neutrophils in the BME were rejuvenated, reactivating their suppressed antibiofilm function. The combined approach of heat stress-triggered iron interference and iron-nutrient immune reactivation resulted in the elimination of more than 95% of bacterial biofilm infection.[226] This study presented a promising antibiofilm strategy that utilizes the unique properties of nanomaterials, photothermal effects, and iron regulation to combat bacterial biofilm infections effectively. The IJIT approach offers a potential solution to the challenge of treating persistent and antibiotic-resistant biofilm-related infections. Lin et al. introduced a novel approach to combat bacterial infections and expedite wound healing. They utilized hollow silver-gold alloy NPs loaded with the photosensitizer Ce6 (Ag@Au-Ce6 NPs), which were designed to integrate MPTT and PDT. Ag@Au-Ce6 NPs were effective in killing bacteria, including both free-floating and surface-colonizing bacteria on wounded skin. The combined use of MPTT and PDT contributed to efficient bacterial eradication. Treatment with Ag@Au-Ce6 NPs promoted various aspects of wound healing, including the migration of epithelial cells and the formation of new blood vessels.[227] The results of this study suggest that Ag@Au-Ce6 NPs hold significant promise for biomedical applications due to their ability to combat bacterial infections and enhance wound healing. The study underscores the potential of these nanoparticles for future medical applications.
Mei et al. presented a strategy for eradicating bacterial-associated infections (BAI) at all stages. They introduced a biofilm microenvironment (BME)-responsive copper-doped polyoxometalate clusters (Cu-POM) combined with MPTT and macrophage immune reactivation. The designed Cu-POM nanoclusters that respond to the specific conditions of the biofilm microenvironment (BME) can serve a dual function in CDT and MPTT. The increased flux of Cu-POM into bacterial cells resulted in intracellular Cu-POM overload. This interferes with bacterial metabolism, particularly the tricarboxylic acid (TCA) cycle, and leads to the accumulation of peroxides, ultimately causing a cuproptosis-like death in bacteria. The study demonstrated that CDT reactivated macrophages, enhancing their ability to scavenge planktonic bacteria that may escape from disintegrating biofilms. This is achieved through increased chemotaxis and phagocytosis.[228] The combination of Cu-POM-induced bacterial cuproptosis-like death, coupled with the reactivation of macrophage immune responses, facilitates the clearance of BAIs at all stages, providing a comprehensive approach to infection control. Zhao et al. developed a versatile hydrogel dressing (rGB/QCS/PDA–PAM) with skin adaptiveness for treating infected wounds effectively and safely. The hydrogel dressing was composed of various components, including phenylboronic acid-functionalized graphene (rGB), oxadiazole-decorated quaternary carboxymethyl chitosan (QCS), and a polydopamine–polyacrylamide (PDA–PAM) network. These components were integrated through multiple covalent and noncovalent bonds. The hydrogel exhibited flexible mechanical properties, making it suitable for use on dynamic wounds. It adhered well to tissue and possesses excellent self-healing capabilities. The presence of phenylboronic acid on the surface of rGB allowed the hydrogel to specifically capture bacteria. This property was particularly useful in targeting and controlling infections. QCS enhanced bacterial vulnerability to MPTT. The hydrogel demonstrated efficient MPTT antibacterial activity. When applied to MRSA-infected wounds in vivo, the hydrogel dressing accelerates tissue regeneration. It promoted the growth of an intact epidermis, encouraged collagen deposition, and facilitated angiogenesis.[229] The hydrogel dressing is a versatile solution that exhibits inherent antibacterial activity. Its adaptability to dynamic wounds, specific bacteria capture, and effective MPTT make it a promising option for treating wounds infected with drug-resistant bacteria. This research has significant potential for clinical applications in wound care.