Photoactive antimicrobial nanomaterials

Yonghai Feng a, Lei Liu *a, Jie Zhang a, Hüsnü Aslan b and Mingdong Dong *b
aInstitute for Advanced Materials, Jiangsu University, Zhenjiang 212013, China. E-mail: liul@ujs.edu.cn
bInterdisciplinary Nanoscience Center, Universitas Arhusiensis, Arhus 8200, Denmark. E-mail: dong@inano.au.dk

Received 10th July 2017 , Accepted 6th October 2017

First published on 9th October 2017


Pathogenic microbes cause infections and are excellent at adapting to the disinfection strategies that address their biochemistry. The growth in number of drug resistant superbugs is alarming, and has attracted attention to alternative solutions. In recent years, researchers have put effort into designing nanomaterials with activatable antimicrobial properties initiated by light irradiation. The underlying mechanisms of these nanomaterials' photoactivatable antimicrobial effect may vary from reactive oxygen species generation, to heat production or pH variation in procedures like photocatalysis, photodynamic therapy, photothermal lysis and photoinduced acidification. In this article, we review the photoactive nanomaterial solutions for fighting against microbial diseases, especially bacterial infections. This Review shines light on the fundamental principles, important developments, promising applications, and limitations of current technologies as well as open questions that these methods may answer or help to answer.


1. Introduction

Food, drinking water, medical equipment, or any other environment contaminated by only a few bacteria can cause common and rare health threats due to the high adaptability and reproductive rate of bacteria.1–4 In the last few decades, antibiotics have been found to be the most effective solution to treat pathogenic bacteria, which has lead to the widespread application of antibiotics in the case of pathogenic infections. However, with the overuse of antibiotics, many multidrug resistance (MDR) bacteria, such as methicillin resistant staphylococcus aureus (MRSA), vancomycin resistant staphylococcus aureus (VRSA), and vancomycin resistant enterococcus (VRE), have now developed through genetic mutations, becoming one of the greatest health challenges, since current antibiotics are found to have less or no effect on MDR bacterial infections.5,6 Finding new long-term solutions for bacterial control and destruction, which could integrate biological methods with novel tools, is absolutely required.

There are several nondrug sterilization methods in place to kill pathogens, however most of them lack localization and activation control or are simply not applicable in vivo.7–18 With the development of nanotechnology it became possible to utilize nanomaterials as antimicrobial agents, which can be activated by light irradiation ranging from the ultraviolet (UV) to near infrared (NIR) spectrum. Due to their low cost,19,20 high throughput,21 excellent yield,20,21 tunable properties,22,23 multifunctionality,24,25 controllability,24,25 and fast effect,19,22,24,25 they have been recognized as an optimal candidate for defeating even the most challenging pathogens. The use of such nanomaterials has shown great potential in many antibacterial applications ranging from food protection26,27 to water treatment,19 textiles modification,28,29 coatings for medical devices and instruments,26,30 and even the treatment of localized bacterial infections and stimulation of tissue integration,31 through photocatalytic disinfection,19 antimicrobial photodynamic therapy,21 photothermal bacterial lysis,22 and light-induced acidification.32 In this review, we focus on the recent development of nanomaterials used for photoinduced inactivation of pathogenic bacteria as listed in Table 1. The relationship between these nanomaterials and light irradiation, the possible mechanisms of the photoactivatable antimicrobial effect and the potential of using these materials for the control of infections are discussed in detail.

Table 1 A summary of photoactive antimicrobiocidal nanomaterials
Mechanism of action Nanomaterials/approaches Ref. Comparative performance parameters of representative examplesa Remarks
Representative example Light wavelength (λ) and power density (P) or light dose (LD) Dose of nanomaterials Type of bacteria and disinfection efficiency
a The data of comparative performance parameters of representative examples were chosen from the reference in each row of the Ref. column in Table 1.
Photocatalysis Titanium dioxide TiO2 nanoparticles 19, 26, 30, 46–48 P2548 λ > 400 nm; P = 24 W 1 mg mL−1 E. coli (100%, 1 h) Titanium dioxide (TiO2) is a promising UV light based semiconductor photocatalyst. Non-metal doping, noble metal and transition metal deposition, coupling semiconductors and morphology change can extend the optical response of TiO2 into the visible region
TiO2 nanorod spheres 23 TiO2-90023 λ > 400 nm; P = 100 W m−2 0.1 mg mL−1 E. coli (82%, 2 h)
N, S, I, Fe, Mn, or Co etc. doped TiO2 20, 48–52 N, S co-doped TKP 10220 λ = 330–400 nm; P = 30 W m2 1 mg mL−1 E. coli (100%, 1 h)
AgX deposited TiO2 53 and 54 Ag/AgBr/TiO253 λ > 420 nm; P = 350 W 0.2 mg mL−1 E. coli (100%, 1 h)
Metal (Pt, Pd, or Ag) or semiconductor (SnO2, ZnO, or CuO) coupled TiO2 55 and 56 ZnO/TiO2 nanofibers55 λ = 312 nm; P = 6 W 1 mg mL−1 E. coli (100%, 1 h)
Zinc oxide ZnO with different morphologies 58 and 59 Cauliflower-like ZnO58 λ = 365 nm; P = 25 W 0.4 mg mL−1 E. coli (100%, 1 h) Zinc oxide based materials have been found highly attractive in the photoinactivation of microorganisms under UV or VIS irradiation for its nontoxicity and low-cost synthesis
Metal (Au) or nonmetal (F) doped ZnO 60–62 ZnO/Au4% nanostructure60 Solar simulator (model 91190–1000) 0.1 mg mL−1 E. coli (>98%, 10 min)
Graphene oxide GO/semiconductor composites 63–68 GO–CdS composites67 λ > 420 nm; P = 100 mW cm−2 0.1 mg mL−1 (100%, 30 min) Graphene oxide (GO) with carboxylic and hydroxyl groups has been found great interest in the construction of GO-based photocatalysts
Sulfonated graphene oxide 70 SGO–ZnO–Ag composites70 λ > 420 nm; P = 100 mW cm−2 0.1 mg mL−1 E. coli (90%, 10 min)
Graphitic carbon nitride Atomic single layer or mesoporous C3N4 71 and 72 Single layer g-C3N471 λ > 400 nm; P = 100 mW cm−2 0.1 mg mL−1 E. coli (100%, 4 h) Graphitic carbon nitride (g-C3N4) has attracted much attention in visible light driven photocatalytic disinfection
C3N4 and GO composites 41 CNRGOS841 λ > 400 nm; P = 193 mW cm−2 0.1 mg mL−1 E. coli (100%, 4 h)
Other inorganic nanomaterials BiVO4, Bi2O3, BOI, CuO, ZnS, ZnIn2S4, CdIn2S4, In2O3/CaIn2O4 and Bi2O2CO3/Bi3NbO7 42, 73–80 BiVO4 nanotubes42 λ > 400 nm; P = 193 mW cm−2 0.2 mg mL−1 E. coli (100%, 5 h) These newly developed semiconductors are stable, effective, low toxic visible light or even near infrared light driven photocatalysts
Antibacterial photodynamic therapy Organic nanoparticles Liposomes 21 and 94 Liposomes-Hp94 λ = 635 nm; LD = 50 J cm−2 0.5 μM MRSA (100%) Biodegradable organic-based nanoparticles are promising nanocarriers for the delivery of PS molecules, which can minimize the precipitation of PS molecules in the bloodstream or aggregation in a polar milieu
Micelles 94–96 Micelle-Hp94 λ = 635 nm; LD = 50 J cm−2 0.25 μM MRSA (100%)
Nanoemulsions 97 and 98 Cationic NE- ClAlPc97 λ = 660 nm; LD = 100 J cm−2 32 μM C. albicans (99%)
Polymeric nanoparticles 100–103 C6–P1103 λ = 664 nm; P = 50 mW cm−2 10 μM E. coli (95%, 10 min)
Hydrogels 104–106 MB loaded PVA–borate hydrogel104 λ = 635 nm; LD = 100 J cm−2 0.05 mg mL−1 MRSA (100%)
Silicon polymers 107–111 MB-bound silicone rubber108 λ = 660 nm; LD = 20 J cm−2 1 mg cm−2 S. epidermidis (100%)
Inorganic nanoparticles Metallic nanoparticles (Au, Ag, Pt) 112–116 MB-gold nanoparticles conjugate112 λ = 660 nm; LD = 24 J cm−2 10−7 mg mL−1 S. aureus (97%) Various inorganic nanomaterials with interesting structures as well as unique physical and chemical properties have been explored to construct photodynamic nanoagents
Mesoporous silica nanoparticles 25, 117–121 DXP and PC zeolite L117 λ = 570–900 nm; LD = 27 J cm−2 2 mg mL−1 E. coli (95%)
Carbon based nanoparticles (carbon nanotubes, fullerene C60, carbon dots, graphene quantum dots) 122–128 Graphene QDs125 λ = 470 nm; P = 1 W 0.2 mg mL−1 E. coli (90%, 15 min)
Magnetic nanoparticles 129 and 130 Nanomagnet–porphyrin 2129 λ > 540 nm; LD = 21.6 J cm−2 5 μM E. coli (100%)
Calcium phosphate nanoparticles 131 and 132 CaP/PSS/mTHPP132 λ = 652 nm; LD = 100 J cm−2 0.335 μM S. aureus (100%) Similarity to the mineral in human bone and teeth
Upconversion nanoparticles 24 UCNPs/MB NPs24 λ = 980 nm; P = 1 W cm−2 0.3 mg mL−1 E. coli (55%, 20 min) Able to trigger PDT under NIR light irradiation
Biomolecules Antibody 139 and 140 IgG–SnCe6140 λ = 632 nm; LD = 8.4 J cm−2 0.025 mg mL−1 S. aureus (100%) Useful for targeting PDT
Antimicrobial peptide 141–144 Eosin-(KLAKLAK)2143 λ > 550 nm; P = 600 W (halogen lamp) 1 μM S. aureus (100%)
Photothermal lysis Gold nanostructures Au nanoparticles 147, 174–177 Antibody-GNPs175 λ = 532 nm; LD = 5 J cm−2 0.1 pM GNPs MRSA (77%) Various gold structures can be used as excellent photothermal agents; their absorbance spectra could be easily tuned by controlling their sizes and morphology. Gold is a rather inert element with reasonable biocompatibility
Au nanorods 152, 183–185 IgG-conjugated gold nanorods152 λ = 785 nm; P = 50 mW 0.04 mg mL−1 P. aeruginosa (75%, 10 min)
Au nanoshells 148, 179 and 188 Core–shell popcorn-shaped Au–NPs179 λ = 670 nm, P = 1.5 W cm−2 0.08 mg mL−1 MDR Salmonella (100%, 10 min)
Au nanocages 149 AuNC@PDA149 λ = 808 nm, P = 1.67 W cm−2 4 nM S. aureus (100%, 10 min)
Au nanopolygon 150 Au@van150 λ = 808 nm, P = 200 mW cm−2 1.125 mg mL−1 E. coli (100%, 5 min)
Au nanograils 151 Au nanograils array151 λ = 830 nm, P = 120 mW cm−2 S. aureus (84%, 1 min)
Carbon nanomaterials Carbon nanotubes 153–158 dsSWNT153 λ = 1064 nm, LD = 3 J cm−2 0.2 mg mL−1 E. coli (100%) Carbon nanomaterials usually show broad absorbance from UV to NIR with excellent photothermal stability; the toxicity of nanocarbons is closely related to their surface chemistry
Graphene 159–164, 190–192 GOS-melatonin159 λ = 808 nm, P = 7.5 W cm−2 5 mg mL−1 E. coli (100%, 2 min)
Iron carbide nanoparticles 193 Fe5C2193 λ = 808 nm, P = 2.5 W cm−2 0.05 mg mL−1 E. coli (100%, 60 min)
Other inorganic nanoparticles Palladium nanosheets 165 Pd@Ag NSs165 λ = 808 nm, P = 0.5 W cm−2 0.06 mg mL−1 E. coli (100%, 10 min) The recently developed inorganic photothermal nanomaterials have good biocompatibility and high efficiency in photothermal conversion, which will be alternative photothermal antibacterial agent in APTL
Copper sulfide 24 and 166 UCNPs/CuS–Cis NPs24 λ = 980 nm; P = 1 W cm−2 0.3 mg mL−1 E. coli (75%, 20 min)
Lanthanum hexaboride 167 van-LaB6@SiO2/Fe3O4 composite167 λ = 808 nm; P = 2.7 W cm−2 0.25 mg mL−1 E. coli (100%, 5 min)
Silicon carbide 168 SiC168 Potential material for APTL induced by MIR irradiation.
Molybdenum disulfide 169, 194 and 195 PEG-MoS2169 λ = 808 nm; P = 1 W cm−2 0.15 mg mL−1 E. coli (89%, 20 min)
Organic photothermal agents Polyanilines 28 and 170 PVPS:PANI28 λ = 808 nm; P = 2 W cm−2 1 mg mL−1 E. coli (99.9%, 20 min) Significant attention has been focused on the development of organic material based photothermal agents in PTBL due to their excellent biocompatibility, biodegradation, and low cost
Polypyrroles 171 PPy/SiO2-GTA composites171 λ = 808 nm; P = 1.5 W cm−2 0.16 mg mL−1 E. coli (90%, 10 min)
Conjugated polyelectrolytes 172 Conjugated polyelectrolytes (P1)172 λ = 808 nm; P = 0.75 W cm−2 0.2 mg mL−1 E. coli (100%, 6 min)
Photoinduced acidification Photoacids Merocyanine 32 MEH32 λ = 470 nm; P = not mentioned 500 μM MDR P. aeruginosa (99%, 1 h) Various newly developed mPAHs find great potential in bacterial inactivation; more research on their efficacy in photoinduced disinfection, biocompatibility and biotoxicity remain to be studied
Hybrid combination therapeutic approaches Phototherapy/antibacterial materials PTBL/silver release 165, 177, 183 and 184 Au@Ag@Au NRs184 λ = 785 nm, P = 50 mW cm−2 0.01 E. coli (100%, 20 min) The hybrid combination therapeutic approaches have recently attracted much attention because the synergetic effect of hybrid approaches can cause a superior photoinactivation efficiency in killing MDR bacteria as compared to the single therapy method
APDT/CAMP 141–144 PS–peptide conjugates (1c)144 λ = 390–460 nm, LD = 13.5 J cm−2 1.5 μM S. aureus (100%)
PTBL/antibiotic 149 and 167 Daptomycin-loaded AuNC@PDA (AuNC@Dap@ PDA)149 λ = 808 nm, P = 1.67 W cm−2 0.04 nM AuNC@PDA loaded with 4 μg mL−1 of Dap S. aureus (100%, 10 min)
Photoacids/antibiotic 32 MEH/colistin32 λ = 470 nm; P = not mention 0.5 μg mM MEH; 1 μg mL−1 colistin MDR P. aeruginosa (100%, 30 min)
APDT/PTBL UPCNs combined with PS and photothermal agent 24 UCNPs/MB/CuS–Cis NPs24 λ = 980 nm; P = 1 W cm−2 0.15 E. coli (100%, 20 min)
PTBL/peroxidase catalysis PTBL/H2O2 catalysis 169 PEG-MoS2169 λ = 808 nm; P = 1 W cm−2 0.15 mg mL−1 MoS2; 100 μM H2O2 E. coli (100%, 20 min)


2. Photocatalytic disinfection

2.1. Mechanism of action

Semiconductor photocatalysis has emerged as a promising technique for microbial inactivation in various aqueous matrices, including the inactivation of diverse types of bacteria, fungi, viruses, and spores.33–37 It is believed that photogenerated hydroxyl radicals (˙OH), superoxide radicals (˙O2), singlet oxygen (1O2), and electrons (e) can cause damage within the target organism and finally result in the death of the organism, as shown in Fig. 1. In the photocatalytic disinfection process, the ˙OH can cause the peroxidation of lipids in the outer cell wall and the damage of cell organelles and DNA inside the cell (Fig. 1a), which is proposed as the key mechanism for photocatalytic disinfection.19,38–40 The cell damage caused by ˙O2 and its oxidation product 1O2 is also believed to be another reason responsible for bacterial inactivation (Fig. 1b and c).20 Bacterial cells can also be photocatalytically inactivated under anaerobic conditions without O2 participation (Fig. 1d).41–43 In such cases, the bacterial cell acts as an electron acceptor and the photogenerated e can enter the bacterial cell directly, leading to reductive cell inactivation by e which functions as the reactive species.41–43
image file: c7tb01860f-f1.tif
Fig. 1 Schematic illustration of photocatalytic disinfection under light irradiation.

2.2. Photocatalysts

Various semiconductor materials can be used in photocatalytic disinfection under UV or visible light (Vis) irradiation, which mainly include metal oxides, e.g. TiO2, ZnO and CuO, etc., metal sulfides, e.g. ZnS and CdS, etc., graphene oxide (GO), graphitic carbon nitride (g-C3N4) and their composites and other semiconductors. Compared to the UV active photocatalysts, Vis active photocatalysts attract more interest due to their better solar energy utilization. We will give some examples of UV active photocatalysts and Vis active photocatalysts in the following.
2.2.1. TiO2 based photocatalysts. TiO2 has been used as a biocidal agent via photocatalysis since as early as 1985.44 There have been many recent studies on the inactivation of microorganisms in the presence of pure TiO2 nanoparticles with various crystalline phases under UV irradiation.19,23,26,30,44–46 However, TiO2 is less effective in photocatalytic disinfection under Vis irradiation due to the inherent large band-gap energy and the fast recombination of electron–hole pairs.26,47 To improve the Vis driven photocatalytic activity of TiO2, several approaches have been developed as follows: (1) metal/nonmetal doping such as N, S, I, Fe, Mn, or Co;20,48–52 (2) silver halide (AgX, X = Cl, Br, I) deposition;53,54 (3) noble metal (Pt, Pd, or Ag) or semiconductor (SnO2, ZnO, or CuO) coupling;20,55 (4) synthesis of polymer–TiO2 composites.56 Moreover, changing the morphology of TiO2 can also enhance the Vis absorption of TiO2.23 Bai et al. found that the hierarchical TiO2 nanorod spheres obtained at high calcination temperature favored high photocatalytic antibacterial activity, probably due to good crystallization of the TiO2 nanorod spheres formed at high calcination temperatures, facilitating the Vis absorption.23 These approaches are mainly used to decrease the band-gap energy, delay the recombination time of electron–hole pairs, extend the photo-response of TiO2 in the visible light region, and thus enhance the persistent production of hydroxyl radicals (˙OH), superoxide radicals (˙O2−), singlet oxygen (1O2−), etc.
2.2.2. ZnO based photocatalysts. ZnO based materials have been found to be highly attractive in the photo inactivation of microorganisms under UV or Vis irradiation due to their nontoxicity and low-cost synthesis. As the antimicrobial activity of ZnO has also been observed in the absence of light, it is thus assumed that production of ROS is not the only mechanism of its antimicrobial activity but other factors such as the impact of Zn2+ ions could play an important role as well.29,57 The photocatalytic activities of ZnO usually depend on their surface morphologies,27,58,59 which can also be changed and tailored to a specific application by depositing noble metal nanoparticles (NPs).60 Another effective way of promoting photocatalytic activity is by modifying the band gap. For example, doping with fluorine can significantly improve its Vis driven photocatalytic performance, increase the mobility of ROS carriers and hence enhance the antimicrobial activity of ZnO in environments void of UV radiation.61,62
2.2.3. Graphene oxide based nanocomposites. Graphene oxide (GO) is a promising material for construction of GO-based photocatalysts in terms of GO and semiconductor (GO/semiconductor) nanocomposites due to its good solubility, high surface area, and many negatively-charged active sites on the sheet surface.63–66 GO/semiconductor composites, such as GO/TiO2.63,64 GO/WO3,65 GO/Ag3PO4,66 GO/CdS,67 and GO/Ag3PO4/TiO268 show significantly enhanced photoinactivation of pathogenic bacteria under Vis irradiation owing to the fast charge transfer and the suppression of recombination of electron–hole pairs in such photocatalytic systems. Moreover, the extremely sharp edges of the GO sheets are capable of destroying the bacteria through direct contact interaction with bacteria.69 Recently, Sun et al. have reported a novel hierarchical GO based photocatalyst composed of sulfonated GO (SGO), ZnO, and Ag nanoparticles (SGO–ZnO–Ag) (Fig. 2a and b).70 The photocatalytic disinfection performance of SGO–ZnO–Ag was much better than those of ZnO, SGO–ZnO and ZnO–Ag under Vis irradiation, which could be attributed to the excellent properties: (1) the SGO sheets were beneficial for the charge separation; (2) the Ag enhanced light absorption owing to its surface plasmon resonance (SPR); and (3) the hierarchical structure facilitating the light scattering and reflection (Fig. 2c).70
image file: c7tb01860f-f2.tif
Fig. 2 (a) Schematic illustration of the preparation process of SGO–ZnO–Ag; (b) TEM images of SGO–ZnO–Ag and the inset of the SAED pattern of ZnO (b1–2), HRTEM images of ZnO nanorods (b3) and Ag nanoparticles (b4) in SGO–ZnO–Ag; (c) schematic illustration of the route for SPR and electron transfer (Reprinted with permission from ref. 70).
2.2.4. g-C3N4 based nanocomposites. As a metal-free photocatalyst, graphitic C3N4 (g-C3N4) has attracted much attention in visible light driven photocatalytic disinfection.41,71,72 However, the photocatalytic efficiency of pristine g-C3N4 is still rather low due to the fast recombination of photogenerated electron–hole pairs. To overcome this drawback, several methods have been developed. Yu et al. found that cowrapping g-C3N4 (CN) and reduced graphene oxide (RGO) sheets on crystals of cyclooctasulfur (α-S8) (CNRGOS8 and RGOCNS8) can kill bacteria under aerobic conditions through a photocatalytic oxidative inactivation process and under anaerobic conditions through a photocatalytic reductive inactivation process, as shown in Fig. 3.41 RGO sheets sandwiched in the heterojunction of CN sheets and α-S8 of CNRGOS8 could well facilitate the separation of e and h+ pairs between α-S8 and CN sheets, under aerobic conditions under Vis irradiation (Fig. 3(c1)). However, RGO sheets covering the heterojunction of CN sheets and α-S8 (Fig. 3(c2)) of RGOCNS8 could not mediate charge transportation because the photogenerated e in the CB of CN could not be transferred to the CB of α-S8 effectively. Therefore, the ROSs generated from CNRGOS8 were much higher than those from RGOCNS8, leading to a significantly higher bacterial inactivation efficiency in the case of CNRGOS8.41 In the case of anaerobic conditions, the photocatalytic inactivation efficiency over both CNRGOS8 and RGOCNS8 decreased significantly due to inefficient e trapping by limited O2. However, the photocatalytic inactivation efficiency of RGOCNS8 was still better than that of CNRGOS8, probably due to the outer RGO sheets (with the high mobility of photogenerated e) over RGOCNS8 favoring more injection of e into bacterial cells (Fig. 3c3 and 4).41 Zhao and coworkers found that single layer g-C3N4 showed significant enhancement in Vis driven photocatalytic disinfection, attributed to its efficient charge separation.71 Huang's group fabricated a robust mesoporous g-C3N4 photocatalyst by using cyanimide as a raw material and silica as a template, which also exhibited nice E. coli inactivation under Vis irradiation.72
image file: c7tb01860f-f3.tif
Fig. 3 (a) Schematic illustration of the preparation steps of CNRGOS8 and RGOCNS8 microspheres; (b) SEM images of CNRGOS8 (b1) and RGOCNS8 (b2); (c) schematic illustration of the mechanisms for photocatalytic bacterial inactivation over CNRGOS8 and RGOCNS8 in aerobic conditions (c1 and c2) and in anaerobic conditions (c3 and c4) (Reprinted with permission from ref. 41).
2.2.5. Other inorganic semiconductors. The development of new types of semiconductors, which are required to be stable, abundant, low toxicity and especially active under visible or even near infrared light irradiation, is an emerging strategy in photocatalytic disinfection. Bi-based oxides such as BiVO4,42 Bi2O3,73 and Bi2O2CO3/Bi3NbO7,74 have recently attracted much attention due to their high Vis driven photocatalytic activity. The AB2X4 family of ternary compounds such as ZnIn2S4,75 CdIn2S4,76 and In2O3/CaIn2O477 have been extensively studied in photocatalytic disinfection because they are excellent Vis driven photosensitive semiconductors. A range of alternative materials such as BOI,78 CuO,79 and ZnS80 have also been reported in photocatalytic disinfection.

2.3. Adverse effects of photocatalytic disinfection

Photocatalytic bacterial inactivation is a green and significantly important route for effective water disinfection, especially solar-driven photocatalytic disinfection. Most photocatalysts are nontoxic and harmless to microorganisms without light irradiation. However, some highly efficient metal oxide based photocatalysts such as Ag/TiO2, AgX/TiO2, Au/ZnO and TiO2/GO and metal sulfides such as ZnS, CdS, and CdIn2S4 can lead to serious environmental problems resulting from heavy metal leaching and photocorrosion.20,53,54,67,74 Recent reports display that graphene has potential cytotoxicity and adverse effects on microorganisms and animals because its extremely sharp edges can destroy the cell and its aggregation can capture microorganisms and further limit their growth.69,81–83 For instance, Chen et al.82 found that the hatching of zebrafish embryos was slightly delayed at a GO concentration of 50 mg L−1, although the GO did not cause significant harm to the embryos. Moreover, Akhavan and coworkers reported that a highly efficient GO/TiO2 composite film generated rather high ROS under Vis irradiation, which resulted in significant death of Caenorhabditis elegans nematodes.65 However, under the same conditions, the ROS level generated by TiO2 is unreachable for inactivation of the nematodes.65 Therefore, it is of great importance that the adverse effects of photocatalysts on the environment be taken into account when utilized for photoinactivation of bacteria.

3. Antimicrobial photodynamic therapy (APDT)

3.1. Mechanism of action

Photodynamic therapy (PDT) is originally and widely used as a therapeutic modality for the treatment of oncological pathologies. In recent years, PDT has been regarded as an alternative method for dealing with localized infections irrespective of the causative microorganism and is specifically termed as antimicrobial photodynamic therapy (APDT).84,85 APDT is a process that combines a non-toxic photosensitizer (PS) and a harmless light of appropriate wavelength to promote a phototoxic effect on the targeted cells via oxidative damage.86–89 During the APDT process (Fig. 4), the PS is first localized in the pathogens, and then activated by light of suitable wavelength irradiation.86 After absorbing a photon, the ground-state PS is changed to a short-lived singlet excited state 1PS*, which can then be changed to a long-lived triplet state 3PS* through intersystem crossing, or alternatively return to the ground state by fluorescence emission and/or heat. The excited 3PS* can either transfer its electrons to the surrounding substrates to generate radical ions such as superoxide (˙O2), hydroxyl (˙OH) and lipid derived ions (Type I pathway),87 or transfer its energy to molecular oxygen (3O2) to produce singlet oxygen (1O2) (Type II pathway).88 The generation of radicals (Type I) and singlet oxygen (Type II) is competing, which depends on the solvent, on monomeric or aggregated forms of the PS or on the oxygen concentration.89 The generated radical ions and singlet oxygen initiate oxidative damage of the cytoplasmatic membrane and DNA of bacteria cells.85
image file: c7tb01860f-f4.tif
Fig. 4 Schematic illustration of photodynamic inactivation of bacteria under light irradiation.

3.2. Photosensitizers

A wide range of PS molecules such as porphyrines, phenothiazines, phthalocyanines, and their derivatives have been applied in APDT.90,91 However, most of the currently developed PS molecules are hydrophobic and have poor target selectivity and low extinction coefficients, and need to be activated at relatively short wavelengths, which significantly limits the APDT efficiency in clinical treatment. To overcome these problems, nanoparticle-based APDT has emerged, in which the nanoparticles are used not only to improve the selective delivery and the dispersity of PS in targeted cells, but also to enhance the effectiveness of PDT. Over the past decade, various nanoparticles (Table 1), including organic and inorganic nanoparticles and some biomolecules, have been extensively explored as nanocarriers of PS for APDT.
3.2.1. Organic nanoparticle based photodynamic nanoagents. Biodegradable organic-based nanoparticles such as liposomes, polymeric micelles, nanoemulsions, and polymeric nanoparticles are promising organic nanocarriers for the delivery of PS molecules, which can minimize the precipitation or aggregation of PS molecules in a polar medium and enhance the interaction with the target cell and thus improve the photoinactivation efficiency.92,93 Liposome-delivered PSs usually exhibit higher photodynamic efficacy against bacteria than the free dye due to the higher endocellular concentration of the PS, resulting in tighter binding and more efficient photoinactivation.21,94 Polymeric micelles can physically embed and/or covalently bind to the hydrophobic PS, which is able to prevent the aggregation of the PS and promote the delivery of the PS into bacteria.95,96 Nanoemulsions (NEs) are particularly attractive delivery vehicles for carrying hydrophobic PSs in APDT, which is significantly affected by the type of NE.97,98 For example, a cationic NE entrapped PS (NE-ClAlPc) could significantly kill Candida albicans, while the anionic NE-ClAlPc had no antifungal activity.97 Recently, polymeric nanoparticles have been developed to deliver hydrophobic PSs in PDT due to their high biocompatibility, stable formulation, and easy preparation.99–103 Those polymeric nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA) have also gained great interest in APDT.101,102 For instance, Freitas et al. used PLGA nanoparticles to support methylene blue (MB-PLGA) for APDT of human dental plaque microorganisms in vitro (planktonic and biofilm phase) and in vivo (patients with chronic periodontitis), in which the MB-PLGA was able to diffuse and release MB within biofilms, giving promising treatment of chronic periodontitis under light irradiation with a wavelength of 660 nm.31

Hydrogels are three-dimensional, cross-linked networks of water-soluble polymers with a highly porous structure, biocompatibility, biodegradability and flexible shape. The unique physical properties of hydrogels provide a different approach for delivering PSs in APDT, especially for APDT of wound infections.104–106 A PS-loaded hydrogel is capable of conforming to the contours of a wound and efficiently releasing the PS in a reasonable time, which makes the APDT proceed locally under light irradiation. Once the treatment is finished, the dilated structure of the hydrogel allows for intact removal. These characteristics may facilitate clinical use of APDT. For example, Donnelly et al. fabricated poly(vinyl alcohol) (PVA) hydrogel supported methylene blue (MB) and meso-tetra (N-methyl-4-pyridyl)porphine tetra tosylate (TMP), showing high efficiency in the APDT of MRSA, which could be used as a potential and novel means of curing wound infections.104 Very recently, Spagnul's group have developed new photoactive hydrogels by immobilizing phenothiazinium chromophore on acrylamide-N,N′-methylenebisacrylamide hydrogels.106 The hydrogel was able to inactivate S. aureus and E. coli with white light irradiation and still kept active for four cycles without leaching of the active molecule.106 The gel can be used as an inexpensive practical systems of water disinfection and easily scaled up due to its high versatility.

Silicone polymer is another promising polymeric material with porous structures and surfaces, which is suitable for loading or capping PSs. Silicone polymer has been used in combination with PSs, such as phthalocyanine 4 (Pc4),107 MB,108,109 toluidine blue O (TBO),108 tris(4,4′-diphenyl-2,2′-bipyridine)ruthenium(II) (RDB2+),110 tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) (RDP2+),110,111 [C60]-fullerenes,111 and 1-(4-methyl)-piperazinylfullerene (MPF),111via immobilization or covalent binding for killing of MRSA,107 prevention of biofilm accumulation,108,109 and water disinfection.110,111 These polymers can be potentially used as materials for preparing antimicrobial catheters and for antimicrobial surfaces for other uses in hospitals.

3.2.2. Inorganic nanoparticle based photodynamic nanoagents. Various inorganic nanomaterials such as metallic nanoparticles, silica, iron oxide, and carbon based materials with interesting structures as well as outstanding properties have also been explored to construct photodynamic nanoagents.

Metallic nanoparticles with unique properties, such as Au,112 Ag,113,114 and Pt115,116, have been widely explored as PS nanocarriers for APDT. The conjugation/loading of PS molecules to metallic nanoparticles usually occurs on the surfaces of metallic nanoparticles, either covalently or noncovalently. The large surface area of metallic nanoparticles favored a large loading of PS. The metallic nanoparticles not only act as vehicles for PSs but also improve the photodynamic efficiency of nanoparticle-based PSs. For example, the gold supported MB nanoparticles showed enhanced photodynamic destruction of bacteria due to the SPR of gold nanoparticles.112 Moreover, the morphologies and particles sizes of metallic nanoparticles also affect the APDT activity of the metallic nanoparticle-based PS.115,116 For example, cubic Pt nanoparticles showed much higher efficiency in APDT against S. aureus than hexagonal and unshaped Pt nanoparticles when they were conjugated with gallium tetra-(4-carboxyphenyl)porphyrin (ClGaTCPP), probably due to the cubic Pt nanoparticles having the smallest particle size and the highest singlet oxygen quantum yield.115

Mesoporous silica nanoparticles have been widely used as vehicles for encapsulating various PSs for APDT applications due to their promising biocompatibility, high capacity of PS loading, and ease of surface functionalization.25,117–121 For instance, Strassert et al. reported a multifunctional hybrid material based on zeolite L for the APDT of drug resistant E. coli and Neisseria gonorrhoeae, in which the outer surfaces of zeolite L were functionalized with amino groups and PS and the channels were immobilized with a green-luminescent dye. The amino groups could first facilitate the multifunctional zeolite L to track the living bacteria, then the dyes were able to fulfill the labeling or imaging of the bacteria, and finally the PS could generate toxic singlet oxygen upon light irradiation to kill the bacteria (Fig. 5).117


image file: c7tb01860f-f5.tif
Fig. 5 (a) Illustration of the function, composition, and structure of hybrid nanomaterials; (b) bright-field microscopy, fluorescence microscopy, and SEM images of E. coli with hybrid nanomaterials functionalized with (b1–3) and without (b4–6) amino groups; (c) time-lapse fluorescence microscopy images of E. coli with hybrid nanomaterials under photodynamic treatment; (d and e) photodynamic inactivation efficiency of E. coli and N. gonorrhoeae cells, respectively (Reprinted with permission from ref. 117).

Carbon based nanoparticles, such as carbon nanotubes, fullerene C60, carbon dots, and graphene quantum dots, have also been successfully used as nanocarriers of PSs or directly as PSs for APDT. Among all these carbon nanomaterials, carbon nanotubes have been developed as attractive scaffolds for immobilizing PSs in APDT against bacteria under white light irradiation.122 Pristine fullerenes are highly hydrophobic, and surfaces functionalized with some functional groups attached to fullerenes are thus needed to make them more soluble in water and biological solutions, suitable for APDT applications.123,124 Carbon dots (C-dots) and graphene quantum dots (GQDs) with ultrasmall sizes have recently emerged as novel carbon nanomaterials showing great potential use as APDT agents.125–128

Other inorganic nanoparticles, such as magnetic nanoparticles,129,130 calcium phosphate nanoparticles,131,132 and upconversion nanoparticles (UCNPs),24 have recently been used as alternative carrier systems for the synthesis of functional hybrids for the photoinactivation of microorganisms. Among them, the UCNPs, which are usually lanthanide-doped nanocrystals and are able to absorb light with long wavelength like NIR and emit light with high-energy like UV,133 have attracted much attention in the construction of UCNP based PS nanocomposites (UCNP-PS). As compared to conventional down-conversion PS nanocomposites which rely on UV or Vis for excitation, the UCNP-PS can be activated by NIR, which is significant for PDT since NIR light is in a transparent window for biological tissue. Moreover, UCNP-PSs are more photostable, low toxicity, and free of autofluorescence background, and have been widely explored for PDT of cancer in vitro due to their general features.134–136 More recently, using UCNP-PSs for APDT have also attracted much attention.24,137,138 For example, Yin and coworkers developed a multifunctional core/satellite UCNP-PS nanostructure (UCNPs/MB/CuS–Cis) for photoinactivation of antibiotic-resistant S. aureus and E. coli under NIR irradiation. The UCNPs/MB/CuS–Cis were constructed by using UCNPs (NaYF4:Mn/Yb/Er) as the core to conjugate with the PS (MB) which was then decorated by CuS nanoparticles and Cis on the surface (Fig. 6a and b). The UCNPs/MB/CuS–Cis had the capacity to form singlet oxygen due to the activation of MB (Fig. 6c and d) and generate heat due to the photothermal conversion of CuS (Fig. 6e and f) under 980 nm laser irradiation, which could synergistically kill the drug resistant bacteria with superior photoinactivation efficiency (Fig. 6g, h and i).24 The UCNPs provide an excellent platform for NIR induced APDT, which can expand the application of APDT in the treatment of various bacterial infections that are difficult to be cured by Vis induced APDT.


image file: c7tb01860f-f6.tif
Fig. 6 (a) Schematic illustration of the synthesis steps of UCNPs/MB/CuS–Cis; (b) TEM images of NaYF4:Mn/Yb/Er (b1), UCNPs/MB–NH2 (b2) and UCNPs/MB/CuS–Cis nanoparticles (b3); (c) the emission spectra of different UCNPs; (d) UV-Vis-NIR absorption spectra of UCNPs/MB and UCNPs/MB/CuS–Cis; (e) the effect of UCNPs/MB/CuS–Cis concentrations on the photothermal conversion; (f) the effect of power densities on the photothermal conversion; (g) photographs of S. aureus (g1–4) and E. coli (g5–8) colonies treated with increasing UCNPs/MB/CuS–Cis concentrations under light irradiation; (h) relative bacteria viability of S. aureus treated with increasing UCNPs/MB/CuS–Cis concentrations under light irradiation; (i) relative bacteria viability of E. coli treated with increasing UCNPs/MB/CuS–Cis concentrations under light irradiation (Reprinted with permission from ref. 24).
3.2.3. Biomolecule–photosensitizer conjugates. Biomolecules, such as antibodies and antimicrobial peptides, have been used to synthesize biomolecule conjugated PSs for targeted APDT. Binding to an antibody offers an effective and simple way of localizing the PS in bacteria. For example, a PS (G-tin(IV)chlorine e6) was able to be directed to the surface of S. aureus when the PS was combined with IgG that could bind to the cell wall protein of S. aureus through the Fc region of the immunoglobulin, realizing the targeted APDT of S. aureus.139 Song et al. have also investigated the effect of APDT against S. aureus using riboflavin-conjugated antibody (R-AB) under UVA light irradiation, showing that the R-AB significantly facilitated the photoinactivation efficiency over riboflavin.140 Combination with a cationic antimicrobial peptide (CAMP) has also been developed as an attractive and effective method for improving the water solubility and the selective delivery of PSs in bacteria due to the cationic and hydrophilic binding of CAMP with the bacterial cells.141–144 For example, a neutral and hydrophobic porphyrin, which was not good at killing Gram-negative bacteria by photoexcitation, was able to efficiently photoinactivate E. coli after being conjugated to CAMPs, such as buforin and magainin, etc.144

3.3. Challenges of APDT

The application of APDT in clinical practice still has several challenges despite the great achievements that have been made in the development of various alternative and functional PSs for targeting pathogenic bacteria. In general, light intensity decreases with increasing penetration depth due to light scattering and absorption when it occurs through various layers. Most PSs are visible light activated molecules (400–700 nm), e.g. phenothiazines (MB and TOB) and porphyrins, etc. However, the tissue-penetration capacity of Vis or UV light is poor, which limits APDT from treating large or internal bacterial infections. In order to maintain or enhance the efficiency of APDT, light with a wavelength of 400–700 nm should be delivered deep into the infected tissue, which however is difficult to achieve by simple visible light sources. Thus, advanced light sources that can penetrate tissue and send forth visible light to activate PSs should be developed. Moreover, the production of ROS species greatly depends on the oxygen concentration surrounding the PS, and the APDT may be ineffective if the infections occur in hypoxic environments like osteomyelitis.145 Furthermore, it is a great challenge for the short lifetimes of ROS to adequately damage bacteria to eliminate the infection while not significantly injuring the host tissue.146 Therefore, a compromise or versatile material must be found regarding the light penetration depth, the PS absorption spectrum, and the localization of pathogen sites as well as the oxygen concentration when conducting APDT. There is still a key point that cannot be neglected, that is, the potential hazards of nanocarriers (especially the newly developed ones) to human beings should be fully investigated even though most of them are biocompatible or degradable because the side effects of them are not presented in the short term.

4. Photothermal bacterial lysis

4.1. Mechanism of action

Photothermal bacterial lysis (PTBL) involves hyperthermia damage to the bacterial cells with the combination of photoabsorbing agents and light. PTBL has been important in the last few years for the elimination of local pathogenic bacterial infections, especially for MDR bacterial infections. In the PTBL process, as shown in Fig. 7, the photoabsorbing nanoparticles (photothermal nanoagents) should be first introduced to the infection site for the selective targeting of the bacterium and then followed by light irradiation with appropriate wavelength. The nanoparticles subsequently absorb the light and quickly transfer the energy into heat through nonradiative relaxation in the surrounding environment. The generated hyperthermal effect eventually causes irreparable damage to bacterial cells, leading to the death of bacteria.
image file: c7tb01860f-f7.tif
Fig. 7 Schematic of photothermal bacterial lysis of bacteria under light irradiation.

4.2. Photothermal nanoagents

Ideal photothermal agents have the following characteristics: (1) strong NIR absorbance and high photothermal conversion;22,147 (2) nontoxicity;148 (3) high bacteria-homing ability,149 which enhance the therapeutic efficacy without rendering toxic side effects. Various nanomaterials (Table 1) including inorganic nanoparticles exhibiting local surface plasmon resonance (LSPR), such as different gold nanostructures,22,147–152 carbon nanomaterials,153–164 and a few other newly developed ones,165–169 as well as some NIR-absorbing organic nanoparticles such as polyaniline (PANI),28,170 polyelectrolyte,171 and polypyrrole,172 have shown great promise in the photothermal destruction of bacteria by visible to NIR radiation. In addition, the photothermal effect of nanoagents can not only be used to directly cook bacterial cells, but is also helpful to combine with other therapeutic approaches to synergistically kill bacteria if a smart nanoplatform is well designed.
4.2.1. Gold based photothermal nanoagents. Owing to the resistance to oxidation and LSPR, gold nanostructures have been widely explored as photothermal agents for PTBL against various types of bacteria. The LSPR of gold nanostructure occurs in Vis to NIR, which depends on the shape, structure and particle size of the nanostructures.173Fig. 8 displays the structures and the typical absorbance spectra of several representative gold nanostructures such as gold nanoparticles (AuNPs),147 gold nanorods (AuNRs),152 gold nanoshells (AuNSs),148 and gold nanostructures with other shapes like cages,149 polygons,150 and grails.151
image file: c7tb01860f-f8.tif
Fig. 8 Plasmonic absorbance and TEM images of various types of Au nanostructures. (a1 and a2) Gold nanoparticles, reprinted with permission from ref. 147; (b1 and b2) gold nanorods, reprinted with permission from ref. 152; (c1 and c2) gold nanoshells, reprinted with permission from ref. 148; (d1 and d2) gold nanocages, reprinted with permission from ref. 149; (e1 and e2) gold nanopolygons, reprinted with permission from ref. 150; (f1 and f2) gold nanograils, reprinted with permission from ref. 151.

AuNPs strongly absorb laser irradiation with a wavelength of ∼530 nm in the visible region, causing damage to bacteria like S. aureus through local hyperthermia effects.147,174–177 However, the absorption and scattering of visible light by biological tissues usually limits the penetration depth of gold nanoparticle-based PTBL. To overcome this drawback, researchers are taking advantage of the aggregation-induced red-shift of gold nanoparticle absorption for photothermal bacterial ablation.178,179 Wang et al. designed and synthesized oval-shaped AuNPs with an LSPR peak of 550 nm conjugated with anti-salmonella antibody. The absorbance band would shift from 550 nm to 680 nm when the Au conjugates were in the presence of Salmonella bacteria solution due to their aggregation into clusters on the bacteria cell.178

AuNRs can be easily synthesized by seeded growth methods and have been widely developed as alternative photothermal agents in PTBL owing to their strong optical extinction in the Vis and NIR region.22,180,181 Various biomolecules are used to conjugate with AuNRs for facilitating bacterial targeting or intracellular delivery.152,182–184 For example, Norman and coworkers constructed a nanocomposite by the conjugation of AuNRs with antibodies specific to Pseudomonas aeruginosa, which was selectively bound to P. aeruginosa cells and significantly reduced the bacterial cell viability after NIR irradiation.152 In order to improve the efficacy in PTBL, researchers are interested in the fabrication of gold based core/shell nanocomposites with silver for synergistic sterilization by photothermal killing and phototriggered silver ion release under NIR irradiation.177,183,184 Using confined convective arraying techniques to fabricate two- and three-dimensional AuNR arrays is another effective route for enhancing the AuNR-based photoheating bactericidal activity as the aggregation of AuNRs could enhance the NIR absorption.180 Recently, Ramasamy's group have designed and prepared recyclable antibacterial Janus particles with the two sides of AuNR arrays and magnetic nanoparticles (MNPs), respectively, which could be recovered magnetically and achieve photothermal ablation of bacteria under NIR irradiation.185

AuNSs, consisting of a thin gold shell surrounding a dielectric core, represent promising agents for the photothermal eradication of bacteria due to their strong SPR, which can be tuned through the manipulation of the dimensions of the dielectric core and the gold shell.186 Huang et al. synthesized magnetic AuNSs (Fe3O4@SiO2@Au) by coating gold on the surface of Fe3O4@SiO2 silica particles prepared by the Stöber method, the SPR peak of which was centered at λmax = 840 nm.187 Fan et al. developed popcorn-shaped iron magnetic core–gold shells (Fe@Au) with a strong absorbance band (λmax = 580 nm) in the visible region.111 These functional magnetic AuNSs can be used for bacteria separation and photothermal lysis of bacteria when they are conjugated with vancomycin or antibodies in the control of a magnetic field.179,187 Recently, Khantamat et al. have prepared SiO2@Au core/shell nanoparticles functionalized with carboxylate-terminated organosulfur ligands and attached to catheter surfaces, showing high efficacy in killing adhered pathogenic E. faecalis using NIR illumination with a wavelength of 810 nm.148

Other gold nanoclusters, such as Au nanocages,149 Au nanopolygons,150 and Au nanograils,151 are capable of absorbing NIR light. When the gold nanocages and nanopolygons are functionalized with antibody or vancomycin, they can selectively bind onto pathogenic bacteria and destroy them under NIR irradiation.149,150 Au nanograils with amazing structures can capture bacteria due to their middle holes and also are capable of rendering photothermal lysis of the bacteria by matching the NIR laser excitation wavelength at 830 nm.151

4.2.2. Carbon based photothermal nanoagents. The sp2 carbon nanomaterials including one dimensional (1D) carbon nanotubes (CNTs) and 2D graphene have also been utilized as photothermal agents for PTBL treatment due to their strong NIR optical absorbance.153–164,188 Besides the strong absorbance of NIR radiation, CNTs have shown high binding affinity to bacteria and can interact with specific cells spontaneously,153 which resulted in the application of functionalized CNTs for photothermal destruction of bacteria selectively.153–158 In 2007, Kim and coworkers investigated both single-walled CNTs (SWNTs) and multi-walled CNTs (MWNTs) for photothermal killing of E. coli.153 Since then, many different groups have studied the selective CNT-based PTBL, using various peptides or antibodies to conjugate with CNTs as photothermal agents that can guide to the bacteria and thus kill the bacteria through the photothermal effect.155–158 Moreover, single-walled carbon nanotubes (SWCNTs) can be used to build SERS substrates for the detection of bacteria by doping other material due to their Raman scattering features such as radial breathing mode (RBM) and tangential mode (G-band). It is reported that SWCNTs covalently bound to gold nanopopcorns and modified with antibodies (mAb–AuNP@f3-SWCNT) could rapidly and selectively detect E. coli in water by SERS and presented impressive photothermal pathogen killing effects.158 Recently, such nanocomposites functionalized for bacterial detection and photothermal therapy have attracted much attention and been rapidly developed for bacteria theranostics.

In recent years, motivated by the success of using CNTs for PBTL applications, graphene has also been developed as an alternative photothermal agent for killing bacteria. In 2011, Akhavan's group first utilized aggregated graphene oxide (GO) nanosheets to wrap E. coli. to isolate them from their living environment, a kind of reversible inactivation, and photothermally inactivate them forever by 808 nm laser irradiation.159 Later, several different groups also studied multifunctional GO nanocomposite-based PTBL in vitro.160–164 For example, Tian et al. demonstrated a multifunctional GO–IONP–Ag nanocomposite with iron oxide nanoparticles (IONPs) and Ag nanoparticles grown on the surface of GO, giving recycling properties and synergistic bacterial inactivation via the APBL and the antibacterial action of Ag.160 Lin's group presented novel GO wrapped gold nanocluster SERS tags with the functions of sensitive Raman imaging and photothermal killing of bacteria by an in situ synthesis strategy.161 To improve the efficiency of GO-based PTBL, the GO are usually reduced to reduced graphene oxide (RGO), which has much stronger NIR absorption.189–192 In a work by Wu and coworkers, a new type of magnetic RGO functionalized with glutaraldehyde (MRGOGA) was reported for efficient trapping and effective photothermal ablation of both S. aureus and E. coli bacteria under NIR irradiation.190 Graphene with a 2D structure and a large surface area offers plenty of room to engineer a variety of multifunctional nanocomposites, promising for bacteria theranostic applications.

With a carbon shell, Hägg iron carbide (Fe5C2) nanoparticles present excellent photothermal conversion efficiency, and can be used as a promising heating source for PTBL. In a recent work by Jin and coworkers, it was reported that Fe5C2 synthesized through a facile one-pot wet-chemical route was explored as an efficient photothermal agent for inactivation of both Gram-negative E. coli and Gram positive S. aureus under 808 nm laser irradiation.193 The Fe5C2 nanoparticles showed 99.9% disinfection of E. coli cells even under the influence of natural organic matter (Humic acid). Moreover, the Fe5C2 nanoparticles still retained good disinfection performance even after reuse five times.193

4.2.3. Other inorganic photothermal nanoagents. Besides Au and C nanomaterials, a number of other newly developed inorganic nanoparticles, which are responsive to NIR and biocompatible, have been investigated as photothermal agents for PTBL applications. For example, palladium (Pd) nanosheets are another kind of noble-metal nanostructures with a tunable absorption band in the NIR region.165 Copper sulfide (CuS) nanocrystals have been demonstrated to be a new type of photothermal therapeutic agent due to the strong absorbance at wavelengths of 900–1000 nm.166 Silicon carbide (SiC) particles have surface phonon resonances in the mid-infrared (MIR) region, which may be an alternative potential promising agent for in vitro photothermal sterilization under MIR irradiation.168 Molybdenum disulfide (MoS2) combined with polymers such as polyethylene glycol and chitosan have been developed as an innovative heating source for wound or subcutaneous abscess antibacterial applications due to their high photothermal conversion under 808 nm laser irradiation, good bacterial binding affinity and biocompatibility.169,194,195 The metal-like plasmonic lanthanum hexaboride (LaB6) nanoparticles are found to have comparable NIR photothermal conversion properties to gold-based nanomaterials, which might have great potential in NIR photothermal therapy due to their relatively low price.196
4.2.4. Organic photothermal agents. As discussed above, the inorganic photothermal agents mainly comprise metal nanoparticles, semiconductor nanoparticles, and carbon-based nanomaterials. However, some of these inorganic agents contain heavy metal elements, which are non-biodegradable and would harm the body. Au and Ag nanoparticles as photothermal coupling agents, which are capable of inducing surface plasmon resonance, have low photostability under long-term laser irradiation. The expense of noble metals limits the wide use of Au- and Pd-based nanoparticles. For these reasons, the development of organic material based PTBL has recently attracted much attention.

Organic dyes that are able to generate heat in the energy dissipation process after NIR light excitation may offer a good platform for photothermal therapy. Many organic dyes with high photothermal efficiency have been explored in photothermal cancer therapy.197,198 However, the application of organic dyes in photothermal disinfection is less reported.

Polyaniline is a very useful conducting polymer with promising conductivity, mechanical flexibility, and low cost, which has been successfully developed as an electroactive material for studying cellular proliferation due to its biocompatibility.199,200 Recently, polyaniline has found interest in the synthesis of novel photothermal antibacterial materials. For example, Hsiao and coworkers demonstrated a smart pH triggered polyaniline based photothermal nanoagent (NMPA-CS) which was composed of chitosan (CS) and polyaniline (PANI) derivatized with mercaptopropylsulfonic acid (MPS) (Fig. 9a). The NMPA-CS was in an aqueous environment at pH of 6.0–6.6 and could transform into colloidal gels at pH of 7.0–7.4 (Fig. 9b–e). This was very important for the phototherapy of the infected acidic abscesses without harming the healthy tissue because the NMPA-CS aqueous solution with the form of micelles could well disperse in the acidic abscesses, while it could not spread to the healthy tissue (pH around 7.0) due to its transformation into colloidal gels, and thus it was able to generate heat upon 808 nm laser irradiation to kill the infected bacteria locally and repair the infected wound without leaving residual implanted materials (Fig. 9a).170 Kim et al. developed a novel photothermal polymer (PVPS:PANI) constructed by poly(vinylpyrrolidone) sulfobetaine (PVPS) and polyaniline (PANI) via ionic interaction, which could be used as an excellent antibacterial surface coating due to good NIR absorption for photothermal lysis of bacteria.28


image file: c7tb01860f-f9.tif
Fig. 9 (a) Schematic illustration of the synthesis of aqueous NMPA-CS and mechanism for the treatment of subcutaneous abscesses by NMPA-CS; (b) SAXS profiles of aqueous NMPA-CS, neat CS, and the fitting results at pH 4.0; (c) SAXS profiles of aqueous NMPA-CS at different pHs; (d) scheme of the structure transformation of aqueous NMPA-CS at different pHs; (e) TEM images of aqueous NMPA-CS at pH 6.3 and 7.0 (Reprinted with permission from ref. 170).

Polypyrrole (PPy) nanoparticles have been developed as efficient photothermal agents for photothermal cancer therapy due to their stability, tunable particle size, and low long-term cytotoxicity.201 Recently, Ju and coworkers have demonstrated the synthesis and application of polypyrrole–silica composites conjugated with glutaraldehyde (PPy–SiO2–GTA) in PTBL, which could target both Gram-positive and Gram-negative bacteria and inhibit the cell growth effectively after photothermal treatment.171

Conjugated polyelectrolytes (CPEs) can also be used as photothermal agents due to their excellent light-harvesting properties.202 However, the application of CPEs in PTBL is restricted by their weak bacterial affinity.203 Modification of some group in CPEs can improve the binding affinity towards bacteria. For instance, Feng and coworkers have synthesized CPEs with quaternary ammonium (QA) terminated side chains (P1) or sulfonate terminated side chains (P2).172 The P1 exhibited much higher photothermal antibacterial efficiency than P2 even though they possessed similar photothermal conversion ability, probably due to the excellent bacterial affinity of P1.172

4.3. Targeting photothermal bacterial lysis

In order to precisely kill the pathogenic bacteria and avoid harming the healthy cells, various approaches have been used to develop novel photothermal agents with specific bacterial targeting. Most researchers are interested in the fabrication of photothermal agents conjugating with antibodies against the corresponding bacteria.149,152,158,174,178,179,182 Some would like to take advantage of the bacterial binding affinity of vancomycin, which can interact with specific peptides located on bacterial cell walls.150,167,187,192 Some others are paying attention to the modification of the surface of photothermal agents with biocompatible molecules or polymers, such as aspartame,177 poly(sodium-p-styrenesulfonate) (PSS),183,184 and poly(allylamine hydrochloride) (PAH),184 which can enhance the binding affinity towards bacterial cells. The utilization of shape-selectivity of photothermal agents for trapping bacterial cells has recently attracted much attention.151,176 For example, Borovička and coworkers have developed a class of AuNP-coated silica shell fragments with specific shape and size for bacterial cells, showing high efficiency in selective photothermal ablation of bacteria.176

5. Disinfection by photoinduced reversible acidification

5.1. Mechanism of action

Recently, it has been found that acidification is an effective way of inactivating bacterial growth because low pH can inhibit the synthesis of intracellular proteins.204 But the conventional acidification routes are not controllable, which can lead to irreversible changes or damage in normal cells. The recently discovered metastable-state photoacid (mPAH), cis-merocyanine (MEH) for example, is a reversible photoacid generator upon optical excitation, which can release protons (H+) that can change the pH of an aqueous solution and form cyclic spiropyran (SP) through a nucleophilic reaction with Vis irradiation of the proper wavelength.205 The SP is a strong acid with a metastable structure and can revert to MEH when the Vis irradiation stops, resulting in the pH of the solution returning to the original level.32,206 Therefore, based on this action, the mechanism of photoinduced acidification for bacterial inactivation can be simply described (Fig. 10). The mPAH is first introduced to the bacterial suspension, and then it can reduce the pH of the bacterial suspension by continually releasing H+ under light irradiation until the bacterial cells are killed completely. Finally, it can recover the normal pH of the bacterial suspension on removing light irradiation.
image file: c7tb01860f-f10.tif
Fig. 10 Schematic diagram of the mechanism of disinfection by photoinduced reversible acidification.

5.2. Metastable-state photoacids (mPAHs)

Photoacids (PAHs) are molecules that can transform into strong acids upon optical excitation, including irreversible photoacids and reversible metastable-state photoacids (mPAHs). For application in disinfection (Table 1), mPAHs are more promising molecules compared to irreversible photoacids since they can increase acidity with light irradiation and revert to the normal level in the dark. In a recent work by Luo and coworkers, a type of photoacid, a merocyanine derivative (Fig. 11), has been synthesized and used for the first time to kill MDR bacteria, Pseudomonas aeruginosa by photoinduced acidification under visible light irradiation.32 After stopping the irradiation, the pH value can recover to the normal level immediately. Moreover, the minimum inhibitory concentration (MIC) of colistin on Pseudomonas aeruginosa can be dramatically reduced to 0.25 mg mL−1 from 8 mg mL−1 when combined with the photoacidification actions, which is very significant to the clinic application of colistin for curing MDR bacterial infections.32 Recently, many groups have paid much attention to the synthesis of novel mPAHs.207,208 It is believed that various newly developed mPAHs will present great potential in bacterial inactivation by photoinduced reversible acidification and more research on increasing the efficacy in photoinduced disinfection and the biocompatibility of new developed agents, and eliminating the biotoxicity of newly developed materials is needed in the future.
image file: c7tb01860f-f11.tif
Fig. 11 (a) Schematic illustration of disinfection by photoacid and colistin under light irradiation; (b) illustration of the reversible transformation between MEH and SP with and without light irradiation; (c) profiles of pH change of MEH solution with or without light irradiation; (d) UV-Vis spectra of MEH with light irradiation at different times; (e) photographs of MDR PA colonies treated with PBS (e1), colistin (e2), illuminated photoacid (e3), and illuminated photoacid and colistin together (e4); (f) relative bacteria viability treated at different irradiation times; (g) relative bacteria viability treated at different pHs (Reprinted with permission from ref. 32).

6. Hybrid combination therapeutic approaches

The combination of light activated therapy with chemotherapy has attracted tremendous attention in recent years for the safe, fast and effective treatment of serious infections or diseases due to the fact that monotherapy is not as effective as we expected. These combinations generally depend on the design and construction of the nanoagents.

6.1. Phototherapy/antibacterial materials

Recently, many antibacterial materials such as silver, graphene, antibiotics, and antimicrobial peptides have been successfully used to combine with photoactions including photodynamic, photothermal and photoinduced acidification for enhanced synergistic antibacterial therapy. The combination method can display high efficiency in disinfection, and meanwhile it can also significantly reduce the dose of antibacterial materials required, and the power density of the laser which will harm the normal tissue over a long irradiation time if the laser power density is too high.

Ag+ release is an alternative and effective antibacterial method that has been widely used to combine with photothermal therapy for synergistic inactivation of pathogenic bacteria because Ag+ release occurs when Au and Ag based photothermal nanostructures are irradiated with a laser. For example, Pd@Ag NSs,164 Au@Ag@aspartame core–nanoparticles,177 Au@PtAg core–shell nanorods,183 and Au@Ag@Au core–shell–shell nanorods,184 have been fabricated and used to synergistically kill several bacterial strains by the actions of photothermal ablation and Ag+ release under light irradiation.

2D graphene including GO and RGO has shown the capacity to inactivate microorganisms due to their extremely sharp edges and the aggregation leading to limit the growth of microorganisms.69,81–83 Thus, the graphene based photothermal agents such as aggregated graphene oxide (GO) nanosheets,159 GO–IONP–Ag nanocomposites,160 GO wrapped gold nanoclusters,161 and magnetic RGO functionalized with glutaraldehyde (MRGOGA),190 can not only inactivate the bacteria but also kill the bacteria under light irradiation.

Antibiotics are still the most effective antibacterial agent. The combination of controlled antibiotic release with photothermal lysis or photoacids is another effective approach for the improvement of inactivation efficacy compared to either therapeutic approach alone.32,149 For example, the MIC of colistin on MDR PA was 8 mg mL−1, when combined with photoacid (MEH) under light irradiation, the MIC of colistin could be reduced to 0.25 mg mL−1. Simultaneously, the combination could kill 99% of MDR PA at 0.5 h, which however needed 1 h for MEH alone under light irradiation.32 Some specific antibiotics like Vancomycin which can interact with bacterial cell walls have been used to fabricate photothermal nanocomposites that can not only show good bacteria-homing ability but also high efficiency in bacterial inactivation under NIR irradiation.150,167,187,192

The cationic antimicrobial peptide (CAMP) is an alternative antibacterial material. The conjugation of PS with a cationic antimicrobial peptide (CAMP) offers not only an approach of localizing the photoactive drug in bacteria but also a synergistic way of killing bacteria because of the APDT and the antibacterial properties of CAMP.141–144

6.2. APDT/PTBL

The recent emergence and development of UCNPs has broken the limitation of APDT that can only be activated by UV or Vis and opens the direction of NIR-based APDT.24,137,138 PTBL is usually conducted under NIR irradiation.22,147–151 Thus, it is possible to combine APDT with PTBL upon NIR irradiation for synergistic inactivation of bacteria if the design and construction of UCNP-based photoactivated nanostructures is smart and reasonable. In a recent work, an UCNP-based nanomaterial was constructed with double functions by modification of CuS as the heating source and MB as the singlet oxygen initiator on UCNPs (NaYF4:Mn/Yb/Er) (UCNPs/MB/CuS–Cis NPs), which facilitated the combination of APDT and PTBL upon 980 nm laser irradiation for synergistic therapy. The bactericidal rates could reach 90% under 20 min irradiation, while it can only reach 45% and 55%, by the APDT (UCNPs/MB NPs) and PTBL (UCNPs/CuS–Cis NPs) of S. aureus alone, respectively.24

6.3. PTBL/peroxidase catalysis

H2O2 assisted by nanomaterials such as V2O5,209 Fe3O4,210 and graphene quantum dots211 has been used as a peroxidase-like action for bacterial disinfection at a much lower H2O2 concentration compared to traditional medical concentrations of H2O2 (volume ratio: 0.5–3%). MoS2 is reported as an intrinsic peroxidase-like catalyst that can be used to catalyze H2O2. Moreover, MoS2 has been recently proved as a promising heating source for bacterial inactivation under NIR irradiation.169,194,195 Inspired by the peroxidase-like activity and the effective photothermal conversion of MoS2, Yin's group has recently developed a safe and effective route of combining PTBL with peroxidase catalysis for synergistic therapy of bacteria infected wounds. It can catalyze the decomposition of H2O2 with a low concentration to generate hydroxyl radicals (˙OH) over MoS2, and meanwhile MoS2 generates a hyperthermal effect under 808 nm laser irradiation.168 PTBL combined with peroxidase catalysis can present more advantages in serious wound disinfections, with the development of peroxidase-like photothermal nanomaterials.

7. Conclusion and outlook

In this Review, we have systematically summarized the recent advances in photo inactivation of pathogenic microorganisms using functional nanomaterials under light irradiation from UV to NIR light, which is a promising and effective strategy for solving the problem of bacterial resistance to available antibiotics. The visible light active semiconductors based on photocatalytic oxidation processes are more suitable for water purification and environmental sterilization. The conjunction of PS with an optimal nanoparticle delivery vehicle, particularly with UCNPs, not only facilitates the solubility, selectivity, and efficacy of PSs in APDT but also breaks the limits of the light penetration through the tissue. Various inorganic and organic NIR-absorbing nanoagents are shown to serve as promising nanoscopic heaters for photothermal bacterial lysis without antibiotics. The emergence of reversible photoacids provides a novel and alternative process for local infection therapy. However, despite the tremendous development of the photoactive antimicrobiocidal nanomaterials and achievement of exciting results reported in the past few years, there are still many challenges ahead for the application of these nanomaterials in clinics. It seems likely that future developments will focus on nanomaterial based Vis or NIR light irradiation, hybrid combination strategies for further improving the antibacterial efficiency and reduction of the biotoxicity of these multifunctional nanomaterials. For the therapy of MDRB infection, it seems likely that the outer irritations such as heat, pH, or ROS towards MDRB will change their metabolism and minimize their resistance to antibiotics, which makes the combination of light based outer irritation and antibiotics possible for a new therapeutic approach for killing MDRB. Besides the above-mentioned applications, the combination of photoactive nanomaterials and bacteria can be alternatively used in various new fields in the future. For example, the good bacteria which fights off the pathogens can be decorated with nanomaterials to enhance the overall antimicrobial effect. Moreover, such a combined system can work as a target specific delivery method for theranostic applications. Another possibility would be energy conversion and storage. Both nanomaterials and photosynthetic bacteria are capable of converting light into chemical energy; in combination they can enhance the conversion efficiency and possibly store the energy as a sort of metalorganic bacterial battery. As an added bonus, combinations can be used with a living color. Nanomaterials can change optical properties with size such as gold nanoparticles and quantum dots, and considering that certain bacteria have color pigments, it is quite realistic to form combined antimicrobial surfaces in our favorite color, changing colors or even glowing in the dark! Besides esthetical reasons color change can be utilized as a multiplatform visual sensor to indicate the existence of the pathogens, and changes in environmental stimuli such as atmospheric gas concentrations, temperature, humidity, light, pH etc. Photoactive nanomaterials are in the early stages of achieving their full potential for practical applications. Even though current utilization methods are at their infancy and only a few combinatory models are proposed, their results offer promising advancement in fighting microbial infections and overall health care.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (No. 51503087, 21606112), China Postdoctoral Foundation Committee (No. 2016M600372), Natural Science Foundation of Jiangsu Province (No. BK20140528, BK20140013, BK20160503), Post Doctoral Fund of Jiangsu Province (No. 1601022A), Natural Science Fund for Colleges and Universities in Jiangsu Province (No. 17KJB180001), and Programs of Senior Talent Foundation of Jiangsu University (No. 15JDG137).

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