Accepted Manuscript

Review

Construction of nanomaterials with targeting phototherapy properties to inhibit

resistant bacteria and biofilm infections

Yuqin Wang, Yingying Jin, Wei Chen, Jingjie Wang, Hao Chen, Lin Sun, Xi
Li, Jian Ji, Qian Yu, Liyan Shen, Bailiang Wang

PII: S1385-8947(18)31945-4
DOI: https://doi.org/10.1016/j.cej.2018.10.002
Reference: CEJ 20064

To appear in: Chemical Engineering Journal

Received Date: 23 May 2018

Revised Date: 14 September 2018
Accepted Date: 1 October 2018

Please cite this article as: Y. Wang, Y. Jin, W. Chen, J. Wang, H. Chen, L. Sun, X. Li, J. Ji, Q. Yu, L. Shen, B.
Wang, Construction of nanomaterials with targeting phototherapy properties to inhibit resistant bacteria and biofilm
infections, Chemical Engineering Journal (2018), doi: https://doi.org/10.1016/j.cej.2018.10.002

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Construction of nanomaterials with targeting phototherapy
properties to inhibit resistant bacteria and biofilm infections
Yuqin Wanga,b#, Yingying Jina,#, Wei Chena, b, Jingjie Wanga, Hao Chena, b, Lin Suna,
Xi Lia, Jian Jic, Qian Yud, Liyan Shene, and Bailiang Wanga, b*
aSchool of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou,

325027, China
bWenzhou Institute of Biomaterials and Engineering, Chinese Academy of Sciences, Wenzhou,

32500, China
cMOE Key Laboratory of Macromolecule Synthesis and Functionalization, Department of

Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China

dState and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College

of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123,

China
eKey Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, the Second

Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou,

325027, China

* Corresponding authors. Fax: +86 577 88017524.

E-mail: wangbailiang2006@aliyun.com (B. L. Wang)

# These authors contributed equally to this work and should be considered co-first authors.

Abstract
The spread of resistant bacteria and the development bacterial biofilm have been two major challenges

in the application of biomaterials, causing device failure as well as tissue infections. The overuse of

antibiotics has become a common cause of the emergence of multiple antibiotics-resistant bacteria.

Besides, biofilm infections are notoriously difficult to treat, as the biofilm matrix provides physical

protection from antibiotic treatment. Recently, nanomaterials with high drug loading capacity, various

types of stimuli responsiveness, smart targeting and small-size are able to increase local drug

concentration and to escape the capture of macrophages. Especially, the loading of drugs to the

nanomaterials enhances chances for macrophage capture which is a serious problem related to

interaction with immune system. Phototherapy including photothermal therapy and photodynamic

therapy has attracted wide attentions in treating infectious diseases as the development of drug-resistant

bacteria and bacterial biofilms. In addition, based on the special microenvironment of bacterial

infections, various construction and modification methods of nanomaterials showed high efficient
antibacterial properties. This review describes the latest advances in the phototherapy strategies to

resist resistant bacteria and biofilms related infections.

Keywords: Drug-resistant bacteria; bacterial biofilms; photothermal therapy; photodynamic therapy;

targeting

1. Introduction
Infectious diseases are health-related issues that have the potential for global catastrophic consequences.

In the past few decades, the emergence of antibiotics has had a huge impact on the treatment of

infectious diseases. [1-6] In spite of the efficiency of antibiotics, the emergence of bacteria resistant to

multiple antibiotics has become a common cause of refractory infectious diseases as the over-

subscribing of antibiotics.[7, 8] For extracellular infections, antibacterial drugs are often quickly

identified and cleared by phagocytes, resulting in the concentration of the drug at the infected site

being too low to treat the infection. [9, 10] In addition, drugs can be partially degraded before reaching

the infected site, which reduces the efficiency of drug. Thus, a repeated or higher dose of the drug is

required for effective treatment of bacterial infections. [11-13] What’s more, drugs will be toxic to

normal cells when they are not targeted to infective site and not responsive to specific stimuli, which

not only reduce the therapeutic effect, but also increase the risks associated with treatment. In

intracellular infections, most of the drugs cannot penetrate the cell membrane effectively, which reduce

the concentration of the drug in the cells. Moreover, there is no guarantee that high concentrations of

the drug in the cells will result in high antibacterial activity. The antimicrobial activity of intracellular

drugs is not only related to the concentration and exposure time of the drug, but also to the physical and

chemical environment in the cells. All of these factors severely reduce the therapeutic effect of

antibacterial drugs and promote the overuse of the drugs, which lead to the emergence of drug-resistant

bacteria.[14, 15]

Pathogens obtain antibiotic resistance by a variety of mechanisms, including gene mutations, cell

membrane permeability changing, long retention times in the cells, development of multidrug efflux

pumps and the emergence of enzymes with the capacity to degrade the drug.[16, 17] Consequentially, a

normal dose of antibiotics may be not effective and a higher dose or repeated administration of the

drug is needed, which eventually lead to a range of side effects such as toxicity.[18, 19] To increase the

local concentration and to prolong the cycle time of drugs, it is necessary to introduce carrier-assisted

drug delivery with targeted and responsive properties.[20, 21] In recent years, more and more

attentions have gradually been paid to the development of nanomaterials due to the high drug-loading

capacity for the high local drug concentration.[13, 22, 23] Because of their small size, nanomaterials
are not easily recognized and removed by macrophages in vivo. Modified nanomaterials can promote

drug targeting to bacterial infective sites to reduce the invalid release of drugs.[24-28]

It is noteworthy that the generation of antibiotic resistance is related not only to the transformation of

the structure and gene mutations of planktonic bacteria,[16, 29] but also to the formation of bacterial

biofilms.[30, 31] More than 80% of human infectious diseases are related to biofilms.[32, 33] Biofilm

is a hybrid of bacterial community wrapped in a bacterial aggregate membrane. The bacteria

irreversibly attach on the surface of inert or active entities, reproduce, differentiate, and secrete

extracellular polymeric substances (EPS) composed of polysaccharides, proteins, nucleic acids, and

lipids.[5, 32, 34-37] On one hand, EPS can protect bacteria against the infiltration of antibiotics and

from the attacking by the host innate immune systems. On the other hand, the bacteria encapsulated in

EPS undergo anaerobic glycolysis in biofilm in the hypoxic environment, which results in ion-channel

turbulence and the production of acid.[38, 39] As a result, it is critical to find new strategies to combat

drug-resistant bacteria and biofilms related infections.

As antibiotics cannot penetrate into biofilms very well, it is usually not effective to destroy biofilms

through routine way of antibiotics delivery.[34] Biofilms protect bacteria from antibiotics which can

also contribute to the formation of bacterial drug resistance.[34, 40] However, antibacterial systems

based on nanomaterials have showed very effective in dealing with biofilms related infections. Many

antibacterial agents have been developed to treat such infectious diseases, including antimicrobial

peptides, inorganic nanoparticles, cationic polymers and photothermal therapy/photodynamic therapy

(PTT/PDT) agents. [41, 42] Especially, phototherapy including PTT and PDT has received

considerable attentions due to the high bactericidal efficiency. Moreover, it will not generate drug-

resistant bacteria as not using antibiotics. As a therapeutic method, PTT has been used to treat many

kinds of diseases such as cancer and biofilms related infections making using of light-absorbing

materials with high light-thermal conversion efficiency. PDT has been used to diagnose and to treat

disease through photosensitizer to produce reactive oxygen species (ROS) in particular singlet oxygen

under appropriate irradiation. These methods can be used to treat infectious diseases caused by

multidrug-resistant bacteria and to delay the development of other drug-resistant bacteria. [43, 44]

The mechanism and wide applications have been reviewed in the reported reviews. [45-47] Herein,

more attentions will be paid to the recent progress of PTT and PDT based on nanomaterials for the

treatment of bacterial infectious diseases in this review. Nanomaterials with targeting property and

responsive to bacterial infections microenvironment or external stimulis also will be discussed.

2. Photothermal therapy
PTT possess high light-thermal conversion efficiency under the irradiation of an external light source

(usually near-infrared light). PTT showed efficient in treating diseases such as cancer and biofilms

related infections. This method can inhibit the development of resistant bacteria and also prevent

biofilms formation by destroying the structure. PTT nanoparticles such as gold nanoparticles[48],

carbon nanotubes[49, 50]， and grapheme[51] are all strong light-absorbing materials. Near-infrared

light with a wavelength range of 700–1100 nm has a good capacity to penetrate tissue while causing

minimal damage to normal tissue, which is regarded as the suitable light wavelength for PTT

therapy[52] .

2.1 Noble-metal nanostructured materials

2.1.1 Au nanoparticles(AuNPs)
Nano-sized gold possesses high plasmon tenability and is considered as an ideal PTT agent for treating

infectious diseases owing to the large-scale preparation, tunable biocompatibility, ease of surface

modification, chemical inertness, excellent optical and electrical properties [53]. Different types of

AuNPs, such as nano-shell particles,[54] half shell nanoparticles, nanorods,[55] and nano-cages have

been developed based on the required production scale. As the nonspecific attacking of PTT therapy, it

can cause damage to normal tissues. Therefore, it is essential to design targeted PTT materials to

reduce harm to normal tissues and to reduce unnecessary waste of resources. As for the biofilms related

infections, anaerobic glycolysis inside the biofilms results in the production of a large amount of acid.

Therefore, designing pH-responsive and targeted NPs has become a common approach for higher

efficient PTT therapy.[56]

To develop pH-responsive NPs, the charges of the designed material surface should be able to be

reversibly changed at different pH values. In this way, charges of NPs surface will change in the

relative acidic microenvironment where the bacterial infections occur. Therefore, NPs gather on the

negatively charged biofilm by electrostatic interactions that enhance the PTT ablation effect under near

infrared light irradiation. Zwitterionic surfaces can also be used to modify NPs. Surface charge

conversion of NPs can be achieved under different pH conditions through modifying the surface with a

strong electrolyte and a weak electrolyte at an appropriate ratio. Thus, a reversible transformation

between free distribution and an aggregated state can be realized. Our group has designed surface-

adaptive mixed-charged zwitterionic AuNPs (Figure 1). A mixture of self-assembled monolayers

(SAMs) was assembled on the surface of AuNPs, which consisted of a strong electrolyte (10-

mercaptodecyl) trimethylammonium bromide (HS-C10-N4) and a weak electrolyte 11-

mercaptoundecanoic acid (HS-C10-COOH) at an appropriate feed ratio [57]. AuNPs were then injected

into a subcutaneous abscess to uniformly distribute in a normal physiological environment (pH = 7.4).
When the acidity of the microenvironment increased (pH = 5.5), the particles gathered and adhered

quickly to the negatively charged surface of the bacteria and aggregated into the methicillin-resistant

Staphylococcus aureus (MRSA) biofilm. AuNPs converted light energy to heat energy under near-

infrared light irradiation and exhibited excellent ablation of biofilms.

Figure 1 (A) Schematic illustration of the pH responsiveness of AuNPs. (B) AuNP-N-C, with positively charged

surfaces in acidic MRSA biofilm (pH ~5.5), effectively adhered to bacteria and rapidly aggregated in MRSA

biofilm, exhibiting great bactericidal effect under NIR light irradiation without damage to surrounding healthy

tissues (pH ~7.4). (C) AuNP-N-S, with negatively charged surfaces, dispersed stably in MRSA biofilm as well as

healthy tissues but showed no bactericidal effect under NIR light irradiation. Reprinted with permission from Ref

[57]. Copyright 2017 American Chemical Society.

Althrough polyaniline (PANI) has been widely used in PTT, the hydrophobic nature limits its

biological applicability. Chitosan and its derivatives have been used to modify PTT materials to

enhance the hydrophilicity of NPs. In addition, chitosan and its derivatives are cationic in acidic

solution, which enables them to target negatively charged bacteria. Hsing-Wen Sung group developed

a polyaniline-conjugated glycol chitosan (PANI-GCS) amphiphilic polymer through covalently

grafting of hydrophobic PANI onto hydrophilic glycol chitosan (GCS, pKa≈6.5) via its highly reactive

amine groups (Figure 2). PANI-GCS has a tendency to self-assemble into NPs in a liquid

environment.[58] In the environment where MRSA exists (pH = 6.3), the surface of PANI-GCS NPs is

positively charged because of the positively charged GCS. The negatively charged MRSA could be

gathered by the PANI-GCS NPs by intense electrostatic interactions, which can be ultimately

eliminated upon NIR irradiation. In normal pH environments (pH = 7.4), neutrally charged PANI-GCS
molecules do not strongly interact with normal host cells, thus avoiding the accumulation of PANI-

GCS molecules and the damage to normal cells.

Figure 2 Schematic illustration of the PANI-GCS NPs. Reprinted with permission from Ref[58]. Copyright 2017

Elsevier.

The above materials are suitable for locally medication. For systematic administration, there is

inevitable risk that drug will enter the blood circulatory system and will be taken by the

reticuloendothelial (RES) system reducing the efficiency of the drug.[59] As a result, some strategies

have been taken to reduce the RES system's intake of drugs. The larger of the NPs (d > 200 nm), the

easier to be taken by macrophages, then the macrophages will move quickly in the blood circulatory

system. In addition, ultra-small PTT NPs can be discharged through the kidneys, reducing the toxicity

and other side effects of drug accumulation in the body. The surface of NPs that appears to be neutral is

also more difficult to be ingested by macrophages.

NPs with low protein adsorption and high water content have a lower chance of experiencing plasma

protein opsonification, leading to the lower swallowing probability by macrophages. Hydrophilic nano-

hydrogels with a diameter less than 200 nm have been widely used in drug delivery due to the small

volume, high water content, and high drug load capacity. Polyacrylamide (PAM)-based nanogels have

advantages in construction of drug delivery systems. Surface modification also has a certain "hidden"

effect. For example, modifying the NPs surface with polyethylene glycol (PEG) is a common way to

prolong the blood circulation time and to lower the toxicity of a drug in vivo.[59] For PTT, high light-

thermal conversion materials such as Au/Ag as the core modified with PEG showed both high

bactericidal effect and a long blood circulation time.

The introduction of hydrophobic antibiotic can achieve a better treatment effect through combination

of PTT and chemotherapy. A double-layer gel can be introduced to solve the problem of poor water

solubility of the hydrophobic antibiotics. The inner hydrophobic core of hydrophobic polystyrene (PS)
was used increase the loading and reservoir of drugs. The outer layer can be modified with a

hydrophilic hydrogel such as a nonlinear PEG chain network or poly(lactic-co-glycolic acid (PLGA) to

increase the stability and to prolong the cycle time of NPs. Such hydrogels based on lower critical

solution temperature (LCST) can be used for the loading and temperature responsive release of drugs.

When temperature is higher than LCST, polymers undergo a phase transition to release the drug.[60]

Responses will occur when the hydrogels are exposed to specific stimulation such as sol–gel phase

transitions, hydrogel degradation, and swelling-shrinking transitions. Hsing-Wen Sung and co-workers

reported an injectable hollow microspheres (HMs) that combined antibiotic therapy and PTT-induced

hyperthermia to possess a synergetic therapeutic efficacy against infectious diseases.[61] These HMs

consists of a PLGA shell and a hydrophilic core loading PTT agent polypyrrole nanoparticles (PPy NPs)

and vancomycin (Van) (Figure 3). Under near infrared (NIR) laser irradiation, the mobility of the

polymer chains increased as the temperature exceeded the glass transition temperature (Tg), which led

to the enhancement of the drug diffusion rate.[62] Meanwhile, locally produced heat also has the effect

of PTT sterilization effect.

Figure 3 Schematic illustrations show the compositions of the novel PTT-responsive HM particles containing Van

and PPy NPs (HM-Van-PPyNPs) and their dual-modality of PTT/antibiotic therapies for treating infected tissues.

Reprinted with permission from Ref[61]. Copyright 2015 Elsevier.

Different bacteria have different shapes, which can be used as a target for antimicrobial treatment.

Vesselin N. Paunov and co-workers[63] have developed a AuNPs to selectively kill bacteria with a

specific shape and size (Figure 4). To construct the PTT colloid antibodies (PCAs), AuNPs were firstly

coated on bacterial cell and silica shells were deposited on the surface, followed by bleaching of the

cells, which resulted in the cell shapes recognizing colloidal antibodies. Once PCAs were incubated

with a mixture of bacteria, they combined selectively with the bacteria with a matching shape. Under

laser irradiation, shape-selective killing of bacteria could be realized. The exploitation of the cell-shape

recognition may have a promising future in selective sterilization and bacterial screening.
Figure 4 (A) Fabrication of the photothermal colloid antibodies (PCAs) by templating AuNP-coated cells with

silica and subsequent silica shell fragmentation and bleaching of the cell templates with Piranha solution. (B)

Experimental setup illustrating the principle of action of PCAs with integrated AuNPs on their inner surface in a

suspension of two types of microbial cells of different morphology. PCAs recognize and bind only to bacteria of

matching shape, which are killed selectively by PTT effect after laser irradiation while the other bacteria in the

mixture remain viable. Gray color signifies dead cells. Reprinted with permission from Ref[63]. Copyright 2013

American Chemical Society.

Figure 5 (A) Schematic diagram illustrating the capability of “multifunctional nanoplatforms” in theranostic

nanomedicine, (B) Scheme showing MDRB separation using a bar magnet after “theranostic nanoplatform”

attachment with bacteria. reprinted with permission from Ref[64]. Copyright 2013 American Chemical Society.

Similar to viral infections, the body will produce antibodies after bacterial infections, which can be

used for targeted drug delivery. Magnetic materials will aggregate in magnetic fields, which can be

combined PTT for high antibacterial efficiency. Modification of the NPs for specifically targeting and

responsive drug release can improve the therapeutic effect of drugs as well as reducing the side effects.

Paresh Chandra Ray and co-workers constructed a novel “multifunctional nanoplatforms”, which

consisted of a magnetic core and a plasmonic shell. Methylene blue-bound aptamer was loaded to

obtain a synergetic PTT and PDT bactericidal effect.[64] This multifunctional nanoplatform was
modified with PEG and a MDRB Salmonella DT104 specific antibody to realize the low toxicity and

targeted bacteria killing effects (Figure 5).

The combination of two sterilization mechanisms is less likely to produce drug-resistant bacteria.

The widely used bactericide AgNPs can work with AuNPs to kill bacteria through release of silver and

plasmonic heating, respectively. [65] Phillip B. Messersmith and co-workers employed a coating of

polydopamine (PD) on an AuNPs for silver shell formation and conjugated anti-bacterial antibodies on

the surface for recognizing bacteria (Figure 6).[66] The bactericidal effect was much better than either

AgNPs or plasmonic heating alone. For PTT, if the NIR laser irradiation power is low, native Au

nanorods are not able to sufficiently elevate the temperature. [67] Recently, core-shell-shell rod shaped

Au-Ag-Au nanorods were explored to tackle the problem (Figure 7). Under low-power NIR laser

irradiation (approximately 785 nm, 50 mW∙cm-2), the PTT conversion efficiency of Au-Ag-Au

nanorods (with a solution temperature of 44 °C) was much higher than that of Au-Ag nanorods (39 °C).

In addition, Au-Ag-Au nanorods showed long-term stability for nearly 16 days. With a low dose of 10

μg∙ml-1, 100% of Escherichia coli were killed after 20 min of irradiation. The Au-Ag-Au nanorods

showed a synergistic bactericidal effect without using antibiotics and avoiding damage to normal

tissues. [68]

Figure 6 Schematic illustration of the polydopamine-based strategy used to synthesize Ab-Au@Ag-NRs.

Reprinted with permission from Ref[66]. Copyright 2014 Wiley.

Figure 7 (A) Scheme for the fabrication and modification of bimetallic core–shell–shell Au-Ag-Au nanorods and

its bactericidal properties investigation. (B) The bactericidal pathway of Au-Ag-Au nanorods including PTT and

silver exposure/release. Reprinted with permission from Ref[68]. Copyright 2015 Elsevier.
2.1.2 CuS Nanoparticles (CuSNPs)

CuS is a potential PTT material for treating bacterial infections. Compared with AuNP, CuS exhibits

excellent photostability without any substantial reduction in optical absorbance for a long time. In

addition, CuSNPs work under a light wavelength of 980 nm, which penetrates deeper into biological

tissues and improves the photothermal ablation effectiveness. Furthermore, compared with AuNPs,[69]

graphene,[70] and carbon nanotubes,[71] the lower cost of CuS makes it an ideal material for

economical mass production.[72] However, the hydrophobicity of CuSNPs and short PTT effective

distance are inherent disadvantages of CuSNPs.[73-75] Modification of CuSNPs to obtain

hydrophilicity and biocompatibility have been done to solve these disadvantages. Cationic antibacterial

molecules not only have the bactericidal effect, but also can target negative charged bacteria.

Quaternary ammonium group is one of the most frequently used cationic antibacterial molecules.

Recently, Chaoxing Li and co-workers reported a novel CuS NPs modified by poly(5-(2-ethyl

acrylate)-4-methylthiazole-g-butyl) (PATA-C4@CuS) which worked at a temperature below 45 °C

avoiding collateral damage to normal cells.[72] The CuSNPs were modified with thiazole derivatives

containing quaternary ammonium groups (PATA-C4) to acquire PATA-C4@CuS, which showed high

stability, biocompatibility, and sensitivity to bacteria (Figure 8). Bacteria aggregate around PATA-

C4@CuS because of electrostatic interactions, leading to an enhanced PTT ablation effect without the

destruction of mammalian cells.

Figure 8 (A) Schematic illustration of PATA-C4 as a combined system for PDT and PTT synergistic elimination

of bacteria. (B) Temperature change of PATA3-C4@CuS at different concentrations. (C) Fluorescence

micrographs of B. amyloliquefaciens stained with AO&EB before and after the treatment of PATA3-C4@CuS.

Reprinted with permission from Ref[72]. Copyright 2017 American Chemical Society.
Figure 9 Schematic illustration of the construction of UCNPs/MB/CuS–Cis as a multifunctional system for

PDT/PTT synergistic therapy of bacteria. Reprinted with permission from Ref[76]. Copyright 2014 Royal Society

of Chemistry.

The synergistic effect of using two different therapeutic modalities showed excellent antibacterial

properties. The conventional therapeutic efficiency of PDT suffers from the limited penetration depth

because this method depends on the penetration of light and NPs to oxygenated tissues.[77] To tackle

this problem, upconverting nanoparticles (UCNPs) have been introduced as nanotransducers to

fabricate UNCP/photosensitizers nanostructures. UCNPs can absorb NIR and convert it into high-

energy photons over a broad wavelength range. In addition, UCNPs have attracted increasing attentions

owing to the features of including photostability, deep penetration, high brightness under low-power

and continuous-wave irradiation. As showed in Figure 9, UCNPs/Methylene blue(MB)/CuS-Chitosan

(Cis) （UCNPs/MB/CuS-Cis）was investigated by Xiaogang Qu and co-workers, which exhibited

excellent antibacterial efficiency against both Gram-positive bacteria (Staphylococcus aureus, S.

aureus) and Gram-negative bacteria (Escherichia coli, E. coli) under NIR light. [76] The

UCNPs/MB/CuS-Cis showed enhanced antibacterial efficiency compared with PDT or PTT alone.

2.2 Graphene
Graphene has an interesting two-dimensional (2D) structure consisting of a single layer of tightly

packed carbon atoms.[78, 79] Graphene possesses a large specific surface area,[80] outstanding

electronic transport,[81] excellent adsorptivity,[82] mechanical stiffness,[83] thermal[84] and chemical

stability, [84] biocompatibility,[85] and optical properties.[86] These properties make it able to absorb

light irradiation and to convert it to heat energy. As a result, graphene has great potential in medical

applications because of its good biocompatibility.

Sandwich-like graphene-mesoporous silica nanosheets (GSs) with good biocompatibility,

hydrophilicity, dispersity, high loading capacity are capable of integrating PTT function.[87, 88]

Xiaogang Qu and colleagues have designed an on-demand drug delivery platform for chemo-

photothermal synergistic treatment of infectious diseases. The drug delivery platform was composed of

gentamicin sulfate (GS) as drug and ferromagnetic nanoparticles(MNPs) with efficient peroxidase-like

catalytic activity, especially refractory bacterial infections in biofilms (Figure 10).[89] Moreover, the
hyaluronidase (hyal) response makes targeted and controllable treatment possible, so as to prevent the

premature release of antibacterial agents and non-specific sterilization of host mammalian cells. To

prevent the premature release of antibacterial agents, hyaluronic acid (HA) is often used to coat the

drug delivery systems. Another NPs developed by the Xiaogang Qu’s group is a photothermal

nanocomposite consisting of graphene oxide (GO) and AgNPs templated with HA (Figure 11). [90]

The use of HA can avoid the toxic effect of AgNPs on mammalian cells. In the case of particular

bacteria that have the ability to release enzyme HAase,[91] HA will be degraded and AgNPs will

release to kill the bacteria. In addition, when exposed to NIR, graphene will convert light energy into

heat to kill bacteria.

Figure 10 (A) Preparation of the on-demand prodrug ascorbic acid (AA) delivery platform AA@GS@HA-MNPs.

(B) Schematic representation of the on-demand drug delivery triggered by bacterial Hyal to inactive bacteria and

to disperse biofilm. Reprinted with permission from Ref[89]. Copyright 2016 Wiley.

Figure 11 Schematic illustration of hyaluronic-acid-templated Ag nanoparticles/graphene oxide composites for

synergistic therapy of bacteria. Reprinted with permission from Ref[90]. Copyright 2017 American Chemical

Society.

Magnetic materials will aggregate in magnetic fields, resulting in high PTT efficiency.

Superparamagnetic properties can be obtained by functionalizing GO with magnetic NPs to form

magnetic reduced graphene oxide (MRGOs). Glutaraldehyde (GA) with the ability to cross-link

proteins in bacteria has been used to capture both Gram-positive and Gram-negative bacteria.[92, 93]
Yong-Chien Ling and co-workers have functionalized MRGO with GA to yield MRGOGA, which

could capture bacteria and exhibit PTT antibacterial efficacy(Figure 12).[93] A membrane integrity

assay and determination of the survival rate demonstrated that an 80 ppm MRGOGA solution could

kill up to 99% of both Gram-positive and Gram-negative bacteria within 10 minutes under NIR laser

irradiation (Table 1). The lateral size determines the antibacterial activity of GO sheets to some

extent.[94] Compared with small GO sheets, larger GO sheets showed stronger antibacterial activity

and undesirable side effects owing to the easy aggregation in the physiological environment. To tackle

this problem, reduced graphene oxide (rGO) has been applied to treat both tumors and infectious

diseases. Vancomycin (Van) was used to capture the drug-resistant bacteria as an affinity ligand. RGO

modified with PEG and Van showed desirable properties, including low toxicity, good biocompatibility,

and high PTT effect. [95]

Figure 12 SEM images of MRGOGA (red arrows) capturing (A) gram-positive S. aureus (yellow arrows) and (B)

gram-negative E. coli bacteria (yellow arrows). Reprinted with permission from Ref[93]. Copyright 2013

American Chemical Society.

Table 1 Survival rate of S. aureus and E. coli for 80 ppm MRGO, MRGOGA, and MCNGA Solution

after Photothermal Treatments under Batch Operation Mode. Reprinted with permission from Ref[93].

Copyright 2013 American Chemical Society.

2.3 Carbon nanotubes

Carbon nanotubes have drawn great attentions in photothermal therapeutics and diagnostics for the past

few decades. Because of the particular photo-absorption properties, carbon nanotubes have strong

absorption under near-infrared light which can effectively convert light energy into heat. It also has

been demonstrated that carbon nanotubes showed no obvious cell toxicity[96] as the similar size of a
single-walled carbon nanotube (SWNT) to biological macromolecules. Carbon nanotubes can

effectively enter cells through the cell membrane via endocytosis, which can be used for drugs and

biological macromolecular delivery.[97, 98] In addition, carbon nanotubes can enrich in bacterial cells

by enhancing the penetration and retention effect (EPR) through binding to receptors on the bacterial

surface.

Previous research has demonstrated that PEG-modified single-walled carbon nanotubes were able

to evade opsonization and phagocytosis by macrophages, thus prolonging the circulation time of the

NPs in vivo. Jin-Woo Kim and co-workers have demonstrated that dextran sulfate coated SWNTs (DS-

SWNTs) possess stealth characteristics similar to PEGylated SWNTs (Figure 13).[99] The DS-SWNTs

functionalized with antibodies can enhance the targeting efficiency. Immunoglobulin G (IgG, an

antagonist of staphylococcal protein A) was covalently conjugated to multi-walled carbon nanotubes

(MWCNTs) which promoted the targeting efficiency of the MWCNTs.[100] Under the irradiation of

808 nm laser, a great and local killing effect was achieved against the IgG-MWCNT- targeted bacteria

(Figure 14). PTT has been developed and applied in treatment of tumors for a long time, which showed

obvious therapeutic effect. Although PTT has recently been used for the treatment of infectious

diseases, the scientific basis and rationale behind PTT have not been well understood and considerable

studies have been performed. It is believed that PTT will play an important role in bacterial infections

treatment.

Figure 13 (A) Schematic illustrating stealth characters afforded by coating SWNTs with DS and PEG. (B) Light

microscopy (left) and EFM (right) images of macrophages with (a) uncoated SWNTs preincubated with opsonins,

i.e., C3b and IgG, (b) uncoated SWNTs preincubated with IgG Ab only, (c) Ab-PEG-SWNTs preincubated with

both opsonins, and (d) Ab-DS-SWNTs preincubated with both opsonins. Reprinted with permission from Ref[99].

Copyright 2013 American Scientific Publishers.

Figure 14 Schematic illustration of the proposed photothermal antimicrobial nanotherapy targeted against MRSA

bacteria using Laser and Ig-MWCNTs. Multi-walled carbon nanotubes covalently functionalized with IgG

molecule (an antagonist of SpA, which is a MRSA membrane associated protein) were selectively delivered (at

various concentrations and incubation times) to MRSA bacteria. Reprinted with permission from Ref[100].

Copyright 2016 American Scientific Publishers.

3 Photodynamic Therapy(PDT)
PDT is a new technique that uses a photodynamic response to diagnose and to treat disease (Figure 15).

The three main features of PDT are light source, photosensitizer (PS) and oxygen. Absorbing photons

of light, the PS molecule becomes activated from the ground state to a short-lived excited singlet state

(1PS*). The excited PS can emit fluorescence and decay back to the ground state, which can be used

for clinical imaging. PS can also be converted into a triplet excited state by intersystem crossing

(3PS*). The PS in the triplet excited state can interact directly with cell membranes and generate

superoxide radicals, hydroxyl radicals, and peroxides (type I reaction), through proton or electron

transfer. Alternatively, excited state PS molecules can transfer energy to nearby oxygen molecules to

produce singlet oxygen (type II reaction). Reactive oxygen species (ROS) obtained from both the type I

and type II reactions can induce autophagy, apoptosis, and necrosis in the cells. It is generally believed

that the type II reaction that produces singlet oxygen plays the major role in these processes.[101-103]

Compared with conventional antibiotics, ROS work through a multi-targeted mechanism, which makes

it less possible to develop bacterial resistance. PDT has many advantages such as small trauma, less

adverse reactions, lower toxicity, curative effect and no development of drug resistance. PDT can also

be used in conjunction with a variety of therapies, including chemotherapy and PTT.

Figure 15 Schematic illustration of a typical photodynamic reaction. Reprinted with permission from Ref[104].

Copyright 2015 American Chemical Society.

Three generations of PSs have been developed, including porphyrins, porphyrin derivatives, and

modified existing PSs.[4] Organic PSs have considerable limitations, including low water solubility,

low stability, poor targeting and low penetrability, which impede the use in clinical application.[105]

Furthermore, because of the short lifetime of 1O2, the diffusion sphere of 1O2 is less than 0.1 μm, which

limits the destruction of biomolecules. Therefore, it is crucial to localize PSs in infectious sites so as to

achieve an effective photodynamic effect. NPs are capable of enhancing the hydrophilicity of PS and

improving the circulation time of PS molecules in vivo.[106] In addition, NPs are able to effectively

prevent the premature degradation of PS in vivo. Some NPs can also provide more oxygen for PDT, as

well as improve the absorption cross section in the near infrared region. Furthermore, different

functional components can be introduced into NPs, including imaging agents, chemotherapy drugs,

targeting molecules, and responsive molecules. Functionally, NPs can be used as carriers of PS, while

some NPs themselves possess photodynamic properties.

3.1 NPs as Carriers

3.1.1 Biodegradable NPs
NPs comprise both biodegradable and non-biodegradable materials. Organic nanoparticles, such as

liposomes, micelles, polymeric NPs, and lipoprotein NPs are all biodegradable, which can be excreted

by enzymatic degradation or an hydrolysis process, avoiding long-term accumulation in organisms

(Figure 16A, B). Both hydrophilic and hydrophobic drugs can be loaded into biodegradable NPs.[107]

Encapsulated within these systems, PS exhibit increased solubility and dispersibility in body fluids,

leading to improved pharmacokinetic properties. Such a carrier could prevent the premature

degradation of drugs and avoid inactivation of the drugs, which should greatly improve the efficiency

of the drugs. In addition, various modifications on the surface can improve drug targeting and reduce

damage to normal tissues.

Figure 16 (A) General PS loading approaches in biodegradable polymeric nanoparticles. (B) PS loading strategies

in liposome and dendrimer. Reprinted with permission from Ref[104]. (B) Schematic of the drug-loaded,

multifunctional, stimuli-sensitive nanoparticulate pharmaceutical drug delivery systems (NDDSs). Reprinted with

permission from Ref[108]. Copyright 2015 American Chemical Society and 2014 Springer Nature.

The surface charge, size, composition, morphology, and hydrophobicity will influence both the

targeting ability and the pharmacokinetics. For instance, PLGA, a widely used biodegradable

copolymer consisting of polylactic acid (PLA) and polyglycolic acid (PGA), improves the PDT activity

by enhancing the production of 1O2 and increasing the plasma circulation time. Periodontal disease or

periodontitis (PD) severely affects human health, which lead to serious oral problems and ultimately

loss of teeth. It is difficult for PS to remain in periodontal tissue for a long time. Hydrogels can be used

to maintain PSs in the oral cavity. The composition of hydrogels affects their mucoadhesive properties.

Chin-Tin Chen and co-workers adjusted the concentration of hydroxypropyl methylcellulose (HPMC)

to obtain a chitosan hydrogel containing toluidineblue O (TBO) with increased mucoadhesive

properties.[109] As the concentration of HPMC increased from 0.25% (F-1 formulation) to 0.5% (F-2

formulation), the mucoadhesive strength increased from 5.13 ± 0.09 to 7.23 ± 0.34 N. However, TBO

alone and the mixture of chitosan and TBO had strengths of 0.77 ± 0.04 and 1.45 ± 0.07 N,

respectively. In addition, surface modification by chitosan improved the sterilization effect of TBO as

well as the targeting function.

However, organic nanoparticles will undergo rapid opsonisation which can be removed from the

systemic circulation by the mononuclear phagocytic system (MPS).[110-112] Modifying the surface of

NPs with poly(ethylene oxide) or PEG can help biodegradable materials evade recognition by the MPS.

The targeting of NPs can be achieved by the surface attachment of antibodies, transferrins or peptides

(Figure 16 C). In addition, the surface of bacteria usually has negative charges, so NPs with positive

charges can target the surface of bacteria via electrostatic interactions, resulting in bacterial aggregation.
Gram-negative bacteria have lipopolysaccharides on the surface, which can also be used as targets in

designing Gram-selective bactericidal materials.

Figure 17 Schematic Illustration of Photodynamic Inactivation Against E. coli by Chol-PEG-PpIX upon Light

Irradiation. Reprinted with permission from Ref[113]. Copyright 2017 American Chemical Society.

In recent years, polymeric micelles have been demonstrated to be ideal carriers to deliver

hydrophobic PS to bacterial infections. Commonly used approaches, such as using hydrophobic

interactions for cell surface engineering, have been used to design targeting drug delivery systems to

treat infectious diseases. As most of the PSs do not interact with Gram-negative bacteria well, novel

modification methods of hydrophobic PS has been developed to interact with bacterial surfaces. Fu-

Gen Wu and co-workers have demonstrated that cholesterol has the capacity to facilitate the

hydrophobic binding between PS and bacterial surfaces. A fully hydrophobic interaction-based PDT

nano-agent, cholesterol-PEG-protoporphyrin IX (Chol-PEG-PpIX) NPs, has been investigated recently

(Figure 17). In aqueous solution, amphiphilic polymers are highly soluble which are able to self-

assemble into micelle-like Chol-PEG-PpIX NPs. When NPs encounter Gram-negative bacteria, such as

E. coli, the structure of NPs will disassemble. Chol moieties can help the PpIX moieties anchor onto

the surface of bacteria with hydrophobic interactions rather than electrostatic interactions, resulting in

severe cell-membrane damage through generation of singlet oxygen (1O2) under the irradiation of white

light. In addition, Chol-PEG-PpIX can enter into bacteria and the bactericidal efficiency can be raised

to more than 99%.[113] This is the first instance of using Chol to facilitate the hydrophobic binding

between PS and bacterial surfaces.

Polysaccharides are one of the main components of the biofilm matrix. Extracellular polysaccharides

are also a major component of the bacterial cell.[114, 115] Therefore, PS designed to target

extracellular polysaccharides can help to achieve localized treatment of bacterial infections. However,

it is difficult to use saccharide recognition for targeting bacteria because of the low affinity between
polysaccharides and PS. Boric acid has been used to overcome this problem. Boric acid is able to form

cyclic boronate five- or six-membered esters with the cis-1,2- or 1,3-diols of carbohydrates. [116] In

addition, boric acid is stable without apparent toxicity, which has received considerable attentions in

the antibacterial field.[117, 118] Anzhela Galstyan and co-workers have reported novel PS

functionalized with boronic acid to target bacteria and biofilm matrices (Figure 18).[119] Silicon(IV)

phthalocyanine (SiPc) was selected as an ideal PS not only because of its high 1O2 yield, long-

wavelength absorption, biocompatibility, and suitable toxicology, but also because of its modification

diversity. Modifications enable the incorporation of SiPc with other characteristics such as aqueous

solubility and target specificity. Poly(vinyl alcohol), a water-soluble polymer with a large number of

hydroxyl groups, can efficiently cross link with boronic acid via the formation of reversible covalent

bonds. This type of material can be used to seal surgical wounds and to prevent wound infections.

Figure 18 (A) Schematic illustration of the interaction between the photosensitizer and polysaccharides of the

bacterial cell membrane and the biofilm matrix; (B) Schematic illustration of the implementation of AGA405 into

a poly (vinyl alcohol) matrix and SEM images of swollen and freeze-dried hydrogel coating. Reprinted with

permission from Ref[119]. Copyright 2017 Wiley.

3.1.2 Non-biodegradable NPs

Mesoporous silica nanoparticles, AuNPs, and multi-functional magnetic particles are non-

biodegradable NPs. The size, morphology, and chemical composition of these kinds of NPs can be

controlled manually. Therefore, these kinds of materials can be combined with light, electricity or

magnetic fields responsive agents for the diagnosis and treatment of bacterial infections diseases.

3.1.2.1 Silica-Based NPs

Silica-based nanoparticles are promising vectors for PDT applications because of their chemical

inertness and stable porosity over a wide pH range, as well as the transparency of the matrix. Other

features, such as stability, hydrophilicity, biocompatibility, and dispersity make silica-based

nanoparticles ideal biological materials. In addition, the shape, size, porosity, and dispersibility of

silica-based nanoparticles are tunable. The surfaces can also be modified with various kinds of

polymers and functional moieties, including PEG, targeting molecules, and imaging molecules. GSs
that possess large pore volumes have been widely used as vectors. As previously discussed, the

Xiaogang Qu’s group have designed a drug delivery system based on graphene-mesoporous silica

nanosheet GS@HA-MNPs (Figure 10) to treat infectious diseases especially refractory bacterial

infections in biofilms.[89] GS@HA-MNPs can act as drug carriers to transport agents and induce a

response to Hyal secreted by bacteria in the microenvironment to degrade HA. Thus the ferromagnetic

nanoparticles (MNPs, Fe3O4) can be released and efficiently catalyze AA into •OH.[120] As a result,

the biofilms were dispersed and the bacteria within were killed.

Figure 19 Scheme for the synthesis of Nc- and Van-modified silica-encapsulated silver-coated gold nanoparticle

(Au@AgNP@SiO2@Nc-Van/NP@Nc-Van). Reprinted with permission from Ref[121]. Copyright 2017 Elsevier.

Van- and naphthalocyanine (Nc)-resistant enterococci (VRE) strains are a great threat to human

health. Van employed as an affinity ligand has been introduced to target VRE. Tingting Jiang and co-

workers reported a silica-based vector, Au@AgNP@SiO2@Nc-Van (Figure 19) for targeting and

photo-inactivate of VRE making use of van ligand. Furthermore, the bacterial strains can be labelled

and monitored by the surface-enhanced Raman scattering (SERS) signals generated by the Au@AgNP

core.[121]

3.1.2.2 Au Based NPs

Gold nanorods (AuNRs) possess some obvious advantages including a high plasmon tenability, the

ability for large-scale preparation, tunable biocompatibility, ease of surface modification, and chemical

inertness, which make AuNRs as ideal bactericidal photodynamic materials.[53] Other properties

including Kostiantyn Turcheniuk and co-workers have developed AuNRs post-coated with a silica

shell containing verteporfin as a photosensitizer (Au NRs@SiO2-VP) (Figure 20). Au NRs@SiO2-VP

were stable and could generate a large amount of ROS when irradiated with a particular wavelength of

light.[122] In addition to gold nanoparticles, fluorescent gold nanoclusters (AuNCs) can be of great
interest for antibacterial diagnostics and therapy.[123-125] Fluorescent AuNCs have been the subject

of intense study owing to their increasing applications in imaging, sensing, and nanomedicine. The

development of multifunctional NC platforms for theranostic applications seems very desirable. A

comparison of Au-nanocage and nanorod-based composites for PDT and PTT treatment showed the

enhanced photoinactivation of S. aureus.[126]

Figure 20 (A) Illustration of the formation of Au NRs @SiO2-VP and (B) Their use for the inactivation of E. coli

UTI89 using PDT with a CW of pulsed-mode laser. Reprinted with permission from Ref[122]. Copyright 2015

Royal Society of Chemistry.

3.1.2.3 Perfluorocarbon-based NPs

The same as tumors the microenvironment of biofilms is oxygenated,[127] as PDT consumes oxygen

and shuts down the vascular transport of oxygen.[128] As a result, hypoxia is common in disease site

and becomes a hindrance to PDT.[129, 130] Yiqiao Hu and co-workers have developed a new strategy

to deal with the poor PDT of PS in low oxygen content environment.[131] This group designed a

device based on perfluorocarbon nanodroplets that have a high oxygen loading capacity to achieve an

enhanced photodynamic effect at a given partial pressure of oxygen in tumor tissues.[132] As a near-

infrared PS, IR780 and perfluorohexane (PFH) were combined to prepare the oxygen self-enriched

PDT (Oxy-PDT) agent LIP (IR780þ PFH) (Figure 21). PFH is self-enriched in oxygen and IR780 can

transfer energy to the oxygen under a near-infrared (NIR) 808-nm laser. In this way, cytotoxic singlet

oxygen could be produced to solve the problem of the low oxygen content in anaerobic infections

environment. Although the original purpose of this experiment was to develop treatments against

tumors, the principle of the material design could be applied to the treatment of infectious diseases.
Figure 21 Structure and design of the Oxy-PDT agent. Photosensitizer and perfluorocarbon are coencapsulated by

lipids. Photosensitizer is uniformly dispersed inside the lipid monolayer and PFC in the core of the nanoparticle.

When irradiated by laser, PS transfers energy to the oxygen enriched in PFH, producing 1O2, resulting in enhanced

tumour inhibition. Reprinted with permission from Ref[131]. Copyright 2015 Springer Nature.

Figure 22 Schematic representation of NPs and surface charge-conversion polymeric NPs for the recognition and

killing of bacteria in the infection microenvironment. Reprinted with permission from Ref[133]. Copyright 2015

Nanotechnology.

Urinary tract infections are common in hospitals and the recurrence of urinary tract infection can

seriously affect both physical and mental health. PDT has great potential in the treatment of urinary

tract infections. However, it is difficult for standard PS to interact with bacteria, because both of them

usually have negative charges. NPs can be used to transfer the charges in the weakly acidic

environment caused by bacteria. Chen Shao and co-workers have investigated the Chlorin e6 (Ce6)

encapsulated polymeric nanoparticles based on 3-(Diethylamino)-1-propylamine (DBPA) and 1,6-

Hexanediol diacrylate (HDDA) into Ce6 ⊂ Poly(HDDA-co-DBPA) -mPEG NPs (Figure 22), which
showed reversible surface charges depending on pH of the environment.[133] PEG can confer aqueous

solubility of the NPs, and the surface of the NPs will be converted to be positively charged in

environments with a particular amount of bacteria. Then the NPs aggregated on the surface of biofilms

and produced a large amount of ROS under laser irradiation at approximately 600-900 nm wavelengths.

In the mouse acute cystitis model, a significant decrease of bacterial cells was found in the urine of

NPs-treated mice compared with mice administered with free Ce6.

3.2 NPs as downconverting PSs

Figure 23 Schematic illustration of fullerene-mediated photodynamic therapy including the Jablonski diagram and

the formation of type I and type II reactive oxygen species (ROS). Reprinted with permission from Ref[134].

Copyright 2010 Elsevier.

Some of the NPs, such as fullerenes, titanium dioxide (TiO2) nanoparticles, and zinc oxide, also

have been widely used as PSs owing to their ability to generate ROS when irradiated under a specific

wavelength of light. Fullerenes are frequently used in treating infectious diseases. In this section, the

applications of fullerene will be discussed. Fullerene is a carbon allotrope with 60 (C60) or 70 (C70)

sp2 carbon atoms arranged in hexagons and pentagons to form into a hollow cage-like fused structure.

Fullerene is unlikely to be taken up by macrophages because the structure is only 7-10 Å in diameter.

The most suitable light for activation of fullerenes is in the blue region or ultraviolet electromagnetic

spectrum because of the extended π-conjugation. Upon irradiation, fullerenes form into a long-lived

triplet state, followed by the generation of ROS, making fullerenes as PS (Figure 23).[134] Fullerenes

showed good photostable ability which are not easily photobleached. However, insolubility and

absorbance of light within a short tissue-penetration depth are obstacles for fullerene application in

PDT. Surface modification and supramolecular approaches, including PEGylation and encapsulation in

micelles, liposomes, or chitosan, can be used to solve the insolubility problem of fullerenes.
Figure 24 Fulleropyrrolidine-photodynamic therapy of S. aureus wound infected mice. (A) Color photographs of

infection sites (wounds created at the mice back) of animals from different experimental groups (a, b, and c) (non-

treated, fullerene-treated with no illumination, and APDT-treated animals, respectively). (B) Bioluminescence

images of mice infected with S. aureus. Non-treated animals (a), treated with sensitizer but kept in dark (b), and

treated after 30 min with fulleropyrrolidine solution and green light (c); (C) Quantification of bioluminescence

values from the images shown in b; *p<0.05; **p<0.01 versus non-treated animals. Reprinted with permission

from Ref[135]. Copyright 2015 Springer.

It has been reported that fullerene can be locally used in antibacterial application which obtain an

up to 3-log reduction of bacteria number upon light irradiation.[134] Recently, fullerene functionalized

with methylpyrrolidium groups[135] showed effective and broad-spectrum antimicrobial properties

(Figure 24). Under average bioluminescent radiance, a 2-log reduction of average rediance difference

between the experimental and control (untreated mice) groups was observed. The wound in the

experimental group stayed visibly clear for three days. Fullerenes with cationic charged arm-like

appendages can rapidly bind to the anionic charged bacteria surface. Long Y. Chiang and co-workers

have synthesized a novel water-soluble decacationic armed C70.[136] In the presence of water, a

balance between the cage and the arm structures is provided by the propyl groups on the quaternary

ammonium salt moieties. The propyl groups overwhelm the hydrophobicity of fullerene cage moiety

and prevent the aggregation of the cages in water. Compared to other PSs, fullerenes work at a longer

wavelength light, which can selectively kill bacteria or cancer cell. Fullerenes promote attachment to

bacteria for a short irradiation time, while a long time of irradiation allows uptake by mammalian calls.

[137]

3.3 NPs as energy transducers

3.3.1 Semiconductor quantum dots (QDs)
Some NPs perform function not only as carriers of PSs, but also take part in energy transfer to the

attached PSs, thus activating the PS indirectly. Semiconductor quantum dots (QDs) show great promise

for PDT applications. QDs possess unique optical and emission properties which range from UV to

infrared region depending on the composition and size of the QD (1-6 nm). Water-solubility and

biocompatibility can be achieved by the surface modification of QDs. QDs also have a large transition

dipole moment, so they are strong light absorbers and good for PDT applications. Similar to energy

donors, QDs can transfer energy to molecules, such as triplet oxygen leading to the generation of ROS.

Colloidal TiO2 is a widely employed photocatalyst for antibacterial studies. However, the required

large band-gap (3.2 eV) for UV activation has hindered the biomedical application of colloidal TiO2.

Efforts have been employed to redshift the light activation region, including doping or coupling TiO2

with narrow band-gap materials or dyes.[138-141] Ya-Ping Sun and co-workers have demonstrated

that carbon QDs (Figure 25) are highly effective at killing bacteria under visible-light illumination.[142]

Figure 25 Cartoon illustrations of (left) a carbon dot, with a small carbon nanoparticle core and the surface

functionalization molecules forming a soft shell; and (right) the photoexcited state species and processes, with the

rainbow color showing fluorescence from the dot surface. Reprinted with permission from Ref[142]. Copyright

2016 American Chemical Society.

Conventional inorganic QDs such as CdSe and CdTe incorporating heavy metal ions are potentially

toxic, which hinders their clinical application.[143] Graphene quantum dots (GQDs), a new kind of QD

with an honeycomb structure composed of single layers of carbon atoms, have recently been

synthesized showing large surface area and excellent thermal/chemical stability.[144] Compared with

conventional inorganic QDs, GQDs possess several advantages, including high fluorescent activity,

excellent solubility and biocompatibility, resistance to photo-bleaching, and ease of production.[144]

Therefore, GQDs are more suitable for bioimaging, biosensing, and other biomedical applications than

conventional QDs. Similar to fullerenes (C60), GQDs in suspension are able to generate ROS upon

photoexcitation.[145] It has been demonstrated that GQDs were able to kill tumor cells exposed to blue
light in a ROS-dependent manner.[146] Antimicrobial properties of GQDs have also been widely

investigated in recent years. Vladimir S. Trajkovic and co-workers demonstrated that GQDs could kill

both MRSA and E. coli through generation of ROS upon photoexcitation (470 nm, 1 W).[147] As ROS

are the main contributors to PDT, the amount of ROS generated is related to the therapeutic effect on

infectious diseases. Jiu-Yao Wang and co-workers have recently synthesized a new kind of GQD

doped with nitrogen which could generate a higher amount of ROS. The nitrogen doped GQD showed

better sterilization effect on E. coli than nitrogen-free GQDs when exposed to a 670 nm laser (0.1 W

cm-2) for only three minutes.[148]

3.3.2 X-ray activatable NPs

It has been reported that to obtain a strong absorption of porphyrins for PDT, the Soret band at

approximately 400 nm is the preferred choice over the Q-band at approximately 600-800 nm. However,

400-nm irradiation cannot be used for clinical applications because of the poor penetration of UV/blue

light. As a result, light with a wavelength longer than 600 nm must be used to activate the weak Q-

band. X-rays can penetrate tissue without the depth limitation, which has been widely used to treat

deep-seated solid tumors. Inspired by the using of X-rays in tumors treating, the same strategy can also

be used to combat deep-seated infectious diseases. However, high doses of X-ray irradiation are

harmful to the human body. To lower the radiation dose, higher doses of PSs are required to acquire

sufficient ROS. In addition, satisfactory photodynamic effect can be achieved by delivering drugs to

the infected site, which can also reduce damage to normal tissue.

GQDs as multifunctional vehicles with high drug-loading capacity, good biocompatibility and

stability have been widely used to transport agents in vivo. As an antibiotic drug, Van is a commonly

used bacterial-targeting ligand based on its strong binding affinity with bacteria. Gu and co-workers

have reported that Van can bind to the D-Ala-D-Ala moieties of the peptide units in the cell walls of

Gram-positive bacteria via hydrogen bonds. Also, Gram-negative bacteria can also be captured by

breaks or deformities the outer membrane of the bacteria when exposed to D-Ala-D-Ala moieties. Tse-

Ying Liu and co-workers have reported a Van-GQDs/PpIX complex that can attach to E. coli through

interactions with Van, which exhibited specific bactericidal effects under a low dose of X-rays(Figure

26).[149] This strategy was shown to be efficacious in treating bacterial infections in deep-seated

tissues and organs.

Figure 26 Preparation and structure of Van-GQDs/PpIX complex. Reprinted with permission from Ref[149].

Copyright 2016 Elsevier.

Figure 27 Comparison of a single photon excitation (A) and a simultaneous two-photon excitation (B). Reprinted

with permission from Ref[150]. Copyright 2017 American Chemical Society.

3.3.3 Two-Photon Absorbing NPs

Two-photon absorbing NPs have been widely used in treating tumors. Recently, research has been

increasingly focused on using two-photon absorbing nanoparticles to treat infections. Some molecules

with two photon absorption (TPA) cross sections are able to simultaneously absorb photos of low

energy and emit photons of higher energy (Figure 27). Conventional PSs with low TPA cross sections

in the biological spectral window (i.e., 700−1000 nm) require high excitation power, which lead to

tissue photo-damage. In addition, the quantum yield of 1O2 may still be low even if the activation of the

PS falls within the NIR range (∼800 nm) because of insufficient triplet formation.[151]

Recently, graphene-based materials with two-photon absorbing properties have become a major topic

for research. As discussed above, graphene can induce PDT property for bacterial infections treatment

when combined with PSs. In recent years, GQDs have been used as two-photon PSs through coupling

with two-photon excitation (TPE) for PDT.[152] In addition, the photoluminescence (PL) mechanism

makes GQDs ideal two-photon contrast agents.[153] Ying-Chih Pu and co-workers used GQDs as two-

photon PSs coupled with TPE. High bactericidal efficacy was achieved using ultra-low-energy

irradiation and a photoexcitation of 800 nm for only 15 s, which resulted in nearly 100% elimination of

both E. coli and MRSA (Figure 28). GQDs with two-photon properties can serve as contrast agents to
observe specimens located deep in a three-dimensional biological environment to eliminate

bacteria.[154]

Figure 28 (A) TPL images at different depths of (a–c) E. coli and (f–h) MRSA were observed from 25 to 75 μm at

a power of 0.704 mW (70.4 nJ pixel-1) by TPE. Images of (d) E. coli and (i) MRSA for extra 10-s photoexcitation

and (e) E. coli and (j) MRSA for extra 15-s photoexcitation at a depth of 75 μm with a power of 2.64 mW (264 nJ

pixel-1). (B) Images and viability of bacteria. After the 15-s photoexcitation laser photoexcitation of (a, b) GQD-

AbLPS-treated-E. coli and (d, e) GQD-Abprotein A-treated-MRSA, Live/Dead kit was used to stain bacteria and

the images were obtained, and (c, f) quantification of viability was determined. Reprinted with permission from

Ref[154]. Copyright 2016 American Chemical Society.

3.3.4 Upconversion nanoparticles (UCNPs)

UCNPs can convert light from low energy to high energy through sequential excitation using multiple

photons via the anti-Stokes emission process (Figure 29). UCNPs are composed of a host lattice of a

ceramic material and transition metal, lanthanide, or actinide ions, such as Yb3+, Er3+, and Tm3+

embedded within the lattice. Upconversion luminescence can be achieved with the use of the above

materials. With both drug delivery and energy conversion properties, UCNPs have been frequently

used in treating deep-seated tumors via PDT as well as antibacterial properties. Yueqing Gu and co-

workers have prepared a UCNPs composed of a cationic N-octyl chitosan (OC) coated UCNP loaded

with the photosensitizer zinc phthalocyanine (OC-UCNP-ZnPc) (Figure 30). This material is composed

of a NaYF4, Yb, or Er core and a NaYF4 shell coated with chitosan and loaded with ZnPc, which

showed excellent PDT efficacy.[155]

Figure 29 Schematic of energy transfer from UCNP phosphor to the attached PS and corresponding energy

diagram. Reprinted with permission from Ref[104]. Copyright 2015 American Chemical Society.
Figure 30 (A) Schematic diagram of OC-UCNP-ZnPc synthesis and its antibacterial activity in vivo. (B) In vivo

anti-MRSA efficacy of OC-UCNP-ZnPc nanoconstructs. (a) Photographs of the mice with MRSA infected skin

abscesses in different treatment groups within 12 days; (b) Changes of the volume of MRSA infected skin

abscesses in different treatment groups within the entire experimental period; (c) Comparison of the in vivo anti-

MRSA efficacy of different treatment groups at day 12. Reprinted with permission from Ref[155]. Copyright 2017

Royal Society of Chemistry.

4 Conclusion
PTT and PDT are promising strategies for the treatment of bacterial infectious diseases, especially the

inhibition of drug-resistant bacteria development and biofilms formation. NPs used for PTT and PDT

possess many advantages such as high PS loading capacity and controlled release to increase the

antibacterial properties. Through surface modification with targeting molecules, NPs will be targeted

onto biofilms or infected sites to improve the utilization of PS and to reduce the toxicity to normal

tissues. Locally and targeted PDT and PTT treatment of infections can effectively reduce the incidence

of bacterial resistance development. In addition, some new developed PDT and PTT such as QDs, two-

photon absorbing NPs, X-ray activatable NPs have showed excellent and high sterilization effects.

In the future, NPs of PTT and PDT higher penetration depth and stability should be paid more

attentions to enhance the treatment efficiency of in vivo study. Also, other stimulus such as ultrasound

responsive NPs and nano sheets such as two-dimensional carbon materials with PDT or PTT functions

will draw more and more attentions.

Acknowledgment
This work was financially supported by the National Natural Science Foundation of China

(31771026, 81771984, 41506091, 21601139), National Key R&D Program (2016YFC1101201),

the Zhejiang National Nature Science Foundation (LQ16B010002), Medical and health science

and technology project of Zhejiang Province (2016YKA139), Zhejiang provincial Public welfare

project(2017C33035) and Science & Technology Program of Wenzhou (Y20160068, Y20160061)

are greatly acknowledged.

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The spread of resistant bacteria and the development bacterial biofilm have been two major challenges.

Biofilm infections are notoriously difficult to treat, as the matrix provides physical protection.

Phototherapy including photothermal therapy and photodynamic therapy has attracted wide attentions.

This review describes the latest phototherapy strategies to resist resistant bacteria and biofilms

infections.