Zinc Oxide Nanoparticle as a Novel Class of Antifungal Agents

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Zinc Oxide Nanoparticle as a Novel Class of Antifungal Agents: Current Advances and Future Perspectives Qi Sun, Jianmei Li, and Tao Le J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b03210 • Publication Date (Web): 09 Oct 2018 Downloaded from http://pubs.acs.org on October 10, 2018

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Journal of Agricultural and Food Chemistry

Title Zinc Oxide Nanoparticle as a Novel Class of Antifungal Agents: Current Advances and Future Perspectives

Author names and affiliations Qi Sun1, *, Jianmei Li1, Tao Le1, ** 1

College of Life Sciences, Chongqing Normal University, No.37 Chengzhong Road,

Chongqing, 401331, People’s Republic of China

CORRESPONDENCE College of Life Sciences, Chongqing Normal University, No. 37 Chengzhong Road, Chongqing, 401331, People’s Republic of China Tel.: +86 23 65910315; fax: +86 23 67301531 E-mail: [email protected] (Dr. Qi Sun); [email protected] (Dr. Tao Le)

ACS Paragon Plus Environment


ABSTRACT 1

Certain types of nanoparticles, especially nanoscale zinc oxide (ZnONP), are widely

2

reported to be capable of the inhibition of harmful bacteria, yeasts and filamentous

3

fungi. The unique physicochemical and biological properties of ZnONP also make

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them attractive to the food industry for use as a promising antifungal agent. This

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review thoroughly introduced the preparation methods and antifungal properties of

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ZnONP, and analyzed its possible antifungal mechanisms. The applicability of

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ZnONP in food packaging, nutritional supplements and as an antimicrobial additive

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are also documented. Moreover, evaluations for biological safety of ZnONP are

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objectively reviewed in this paper. The discussions addressed in this paper not only

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have theoretical significance, but also are conducive to the development of food

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safety, nutrition, and human health. The summarized knowledge and future

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perspectives outlined here are expected to promote and guide the new research

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developing and optimizing the application of ZnONP as a novel class of antifungal

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agents to help improve food quality as well as food safety in the near future.

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Keywords: Zinc oxide nanoparticle; Physicochemical properties; Antifungal activity;

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Mechanism of action; Application; Risk assessment

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INTRODUCTION

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Emerging fungal infections and fungal contamination have been at the forefront of

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worldwide safety affairs in the last few years. Taking the food industry as a notable

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example, fungal contamination cannot only cause the deterioration of product quality,

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economic loss, but also severely threaten food safety and public health. In the

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meantime, improper use of antibiotics nowadays has further aggravated this issue and

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resulting in a noteworthy rise in the prevalence of drug-resistant fungi. For this reason

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scientists around the world are endeavoring to develop various measures to prevent

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and control fungal contamination, including applications of plant essential oils,1-4

27

antimicrobial peptides5-7 and even predatory microorganisms.8,

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methods have been confirmed to have better antifungal performances in the laboratory,

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while exposing some shortcomings like high cost, poor stability, interference with

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food components, and unpredictability in human health risks. On the other hand,

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research on nanotechnology has grown substantially for the last few years. Many

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studies have been devoted to the preparation of new forms for nanoscale particle (NP)

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with anticipated utilizations in all fields of food science, from food processing to

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preservation and nutrient supplementations.10, 11 Nanoparticles are also regarded as the

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most promising substitute for traditional antibiotics in the control of pathogenic

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microbes.12, 13

9

Most of these

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As depicted in Figure 1, a nanoparticle (or nanopowder or nanocluster or

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nanocrystal) is a microscopic particle with at least one dimension less than 100 nm.



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They pose physical and chemical characteristics that differ considerably compared to

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those of macroscale particles.14, 15 In fact, it is not difficult to find published articles

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on NP with good antimicrobial activity, including silver nanoparticle (AgNP),16-18

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nanocarbons such as single-walled carbon nanotube (SWCNT), multiwalled carbon

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nanotube (MWCNT), and graphene materials (GMs).19-22 Among these nanosized

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antimicrobial agents, various AgNP-containing compounds are now commonly used

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in several healthcare products or clinical medicines.23,

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include high price, easy agglomeration in tissue and biological side effects which may

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impede the use of AgNP-based antifungal substances in food field. On the other hand,

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carbon nanomaterials, especially graphene-based NPs, are rapidly emerging as a novel

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class of antimicrobial agents due to their unique physicochemical properties.20 Yet,

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these nanocarbons, like carbon nanotubes, graphene, graphene oxide (GO) and

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reduced GO (rGO), are in their infancy as nano-additives in comparison to AgNP, so

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there are still a lot of uncertainty about their future applications. Economic and facile

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preparation of such nanoscale carbon materials is also a barrier that will need to be

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overcome to ensure the development of antifungal nanoagents. Indeed, compared to

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their conventional bulk counterparts, NPs possess completely different or enhanced

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characteristics such as decreased size, enhanced specific surface area, and thus

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strengthened reactivity. These features make NPs more pronounced and auspicious

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for diverse industrial uses including food field but meanwhile make them a potential

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threat to human health.25 While public awareness about the applications of general

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nanotechnology have ranged from neutral to slightly positive,11, 26 the screening and


24

Disadvantages to AgNP

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development of novel antifungal agents based on NPs with high efficiency, economy,

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and innocuity should be considered in future research.

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Figure 1. Various types of nanoscale materials

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Considering this background, nano-sized zinc oxide particles (ZnONP) are

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currently considered to be the most promising antibiotic nanoscale agent due to their

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unique properties. ZnO has been registered as “Generally Recognized as Safe” by the

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Food and Drug Administration of the United States (21CFR182.8991);27 nanosized

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ZnO may have better biocompatibility than other NPs.28,

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scientific evidence suggests that the use of ZnONP has no or negligible potential

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threat to public health.30, 31 These particles are widely used in sunscreens, toothpastes,

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anti-dandruff shampoos, anti-fouling paints and other modern personal products due

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to their unique physicochemical properties.32, 33 Moreover, ZnONP is valued for its

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putative anticancer activity and for potential in drug delivery.34 Therefore, the global

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production of ZnONP ranks third among diverse metal-containing NPs only after

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silica and titanium dioxides.35 Distinct ZnO-based nanostructures can be obtained


29

Importantly, current


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through various approaches which effectively solve cost issues.36-39 Additionally,

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although the exact mechanisms of action are not yet entirely understood, ZnONP may

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exhibit excellent antiseptic performance compared to other antimicrobial agents due

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to its multimodal manner. For these reasons, scientists and entrepreneurs have already

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identified potential activities and utilizations of ZnONP in many aspects of diverse

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fields.

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Figure 2. Schematic diagram of the scope of the current review

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Despite explosive growth in this area of research, the development of antifungal

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nano-additives for food-related systems is currently very limited. This article aims to

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bridge this information gap by contributing an extensive discussion of the current


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advances about the antifungal activity of ZnONP covering its characteristics and

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preparation methods (see the schematic demonstration in Figure 2). In the subsequent

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sections, we cover topics on ZnONP including antifungal performance, factors related

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with antifungal efficiency, and the major mode of antifungal action. A special focus

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has been given to the antifungal mechanism of ZnONP at the molecular level. We

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further elaborate on the potential applications of ZnONP as a promising antifungal

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additive in different food fields. Concerns about human health with ZnONP are also

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critically discussed based on existing information. Finally, this report concludes with

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a further perspective that ZnONP has developed as a promising nanoscale antifungal

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agent. Hopefully, this article may act as a useful reference for researchers actively

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involved in the fabrication and development of nanomaterial-based antifungal agents.

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BASIC CHARACTERISTICS AND PREPARATION STRATEGIES FOR

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ZINC OXIDE NANOPARTICLE

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In order to understand the antifungal performance of ZnONP, the physico-chemical

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activities of these nanoscale materials should be fully evaluated by some certain

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testing. In fact, ZnONP has received extensive attention owing to their noteworthy

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properties in a variety of fields, including biotechnology, in recent years. ZnONP is a

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known II–VI semiconductor which has a direct wide band-gap (~3.37 eV), high

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excitonic binding energy (60 meV) and various other advantages as shown in Figure 3

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including high transparency, a polar surface, natural abundance and excellent

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photocatalysis.40-43 There are mainly three crystal structures of ZnONP in which



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wurtzite zinc oxide is the most common because of its highest thermodynamic

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stability.44 As an important technological material, ZnONP can be prepared with a

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growing number of synthetic routes. Such preparation strategies can be divided into

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physical methods (e.g. thermal evaporation, ultrasonic irradiation and vapor

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deposition),45, 46 chemical methods (hydrothermal, sol-gel and precipitation)

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biological methods (from plant extracts, microbes and other biomolecules).36, 50, 51

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Recently, great progress has been made in the synthesis of nanostructed ZnO particles

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but each of these reported approaches have their own drawbacks. It is thus extremely

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important to develop other strategies with high efficiency, low cost and

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eco-friendliness to prepare ZnONP at the industrial scale.

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47-49

and

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Figure 3. Properties of nanostructed zinc oxide particle (ZnONP). Flower-like

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ZnONP as shown in inset is fabricated via a facile one-pot precipitation strategy in

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our laboratory.

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INHIBITORY PERFORMANCE OF ZINC OXIDE NANOPARTICLE ON

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THE GROWTH AND METABOLISM OF FUNGI

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The versatility of ZnONP has allowed it be applied as an antimicrobial substance for

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the inhibition of microbial pathogen growth and metabolism. The antibacterial

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activity of ZnO and other metal-containing NPs have been previously reported in a

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vast number of articles. There is no doubt that the sensitivity pattern of fungi to metal

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oxide NPs is very different from that of bacteria due to their distinct biological

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structures. Therefore, the inhibitory effect of ZnONP and other nanosized materials

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on fungi has gradually been given more attention by researchers. Currently,

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prevention and control fungi contamination with nanotechnology is a focus of the

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following studies. A number of literatures have shown that various assays can be

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applied for antifungal testing with NPs in practice, such as agar or broth dilution, disk

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diffusion and the microtiter plate-based methods.52-54 ZnONP can also effectively

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inhibit various pathogenic fungi as listed in Table 1.

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Meanwhile, the synergistic antifungal activity of ZnONP was evaluated along with

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common antibiotics (e.g. ciprofloxacin, ampicillin, fluconazole and amphotericin B).

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Their inhibitory efficiency can be enhanced in combination with ZnONP, which could

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possibly reduce the overuse of antibiotics.70 Moreover, researchers have developed



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various NP-based nanocomposites via surface modification using polymers,

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biomolecules and carbon nanomaterials to reduce toxicity and enhance their

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antifungal activity. For example, Barad et al. have shown that ZnONP coated by

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chitosan-linoleic acid has significant efficacy compared with fluconazole in inhibitory

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action on the growth and biofilm formation of C.albicans.56 It is worth noting that

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many filamentous fungi can produce secondary metabolites known as mycotoxins,

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which can induce immunosuppression, as well as embryonic and even carcinogenic

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effects on human health.71, 72 Thus, the most important application value of ZnONP

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lies in blocking and inhibiting synthesis of mycotoxins.73 For instance, inhibitory

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performance of synthesized ZnONP on mycotoxin production was investigated by

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Hassan and his co-workers.61 They found that the existence of aflatoxigenic fungi and

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aflatoxin production were inhibited by the addition of 8 μg/mL of ZnONP, while the

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inhibitory results were also observed for ochratoxin A and fumonisin B1 when the

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concentration of ZnONP was increased to 10 μg/mL. These findings indicated that the

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involvement of ZnONP in the food matrix may not only effectively inhibit the growth

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of harmful fungi, but importantly decrease the content of mycotoxins produced by

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toxigenic fungi.

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FACTORS AFFECTING ANTIFUNGAL PERFORMANCE

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INFLUENCE OF INTERNAL (NANOPARTICLE) FACTORS

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The physicochemical characteristics of ZnONP play a major role in its antifungal

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efficiency. Various inherent characteristics including particle size, concentration,


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morphology, superstructure as well as surface activity have also been shown to affect

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the application of ZnONP as a nano-additive in food-related products. For both

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fundamental reasons and future applications, internal factors affecting nanoparticle

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antimicrobial performance have been documented in many studies. For example,

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Deepali et al. have found that the inhibitory action of ZnONP on the fungus

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(Fusarium sp.) was concentration-dependent, and this dependency was also affected

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by particle size.63 In a subsequent study, Padmavathy et al. reached to similar

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conclusions that antifungal efficiency of ZnONP commonly increases with a decrease

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of particle size and at enhanced concentrations.28 Moreover, they also reported that

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ZnONP with a smaller particle size could induce more hydrogen peroxide ascribing

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its higher specific surface area, which would further enhance its antifungal efficiency.

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Compared to the large amount of the literature about ZnO acting against bacteria,52,

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74-76

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antifungal activity appears to be more complex considering the bioactivity, crystalline

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structure, concentration of ZnONP and some specific external factors. For example,

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scholars have pointed out that the effect of particle solubility on the inhibition of some

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aquatic microorganisms is more critical than particle size.74 Recently, Hui et al.

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successfully prepared cerium-doped flower-shaped ZnONP through a facile

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microwave-mediated hydrothermal route, and illustrated a morphology-related

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antifungal effect of these crystallites.69 These flower-shaped ZnO crystallites had

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stronger antifungal performance against pathogenic fungi (e.g. C.albicans and A.

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flavus) than pure ZnO crystals. This finding makes clear evident that the crystalline

we speculate that correspondence between nanoparticle size and the respective



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morphology and structure can also affect nanoparticle antifungal activity. The desired

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synthesized ZnONP structures for best antifungal activity could be made by

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regulating the synthesis parameters, such as surface stabilizing agents, solvents,

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precursor types, temperature as well as preparation ways.77, 78 Actually, Prasun et al.

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have revealed that the microwave-assisted green synthesis could prepare ZnONP with

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higher antifungal efficiency in contrast to those obtained by conventional chemical

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methods.60 The shape-dependent antifungal activity of NPs has also been examined in

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a few studies, and the correlation between both should be illustrated in terms of the

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presence of different active facets in metal oxides.79 In this regard, polar facets of

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nanostructed ZnO seem to be able to improve particle antifungal activity. The higher

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level of polar surfaces has more oxygen vacancies, which consequently can generate a

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higher amount of reactive oxygen species (ROS).80,

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biological activities attributing to their highly reactivity and oxidizing properties. In

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addition, the inhibitory role of ZnONP on the tested microorganism may be closely

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associated with particle surface defects and orientations.28 It has been proposed that

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the orientation of nanosized ZnO possesses higher antimicrobial efficiency due to its

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various randomly oriented spatial configurations compared to those of regularly

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arranged structures.79, 82, 83 However, in another comparative study, Tam et al. came to

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conclusion diametrically opposed to the above results.84 While no consensus has been

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reached yet, these results provide an encouraging insight on the role of affecting

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factors in nanoparticle antifungal activity.

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INFLUENCE OF EXTERNAL FACTORS

81


ROS are proven to affect

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Metal oxides, particularly for ZnONP, are well-known to exhibit high photocatalytic

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efficiencies. The application of ZnO photocatalysts on decomposing organic

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pollutants in contaminated environment has been demonstrated in many studies.85, 86

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Theoretically, the illumination factor for ZnONP should be closely related to the

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performance of ZnONP against harmful fungi considering its photocatalytic property.

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As illustrated in Figure 4, photo-excitation with energy greater than 3.37 eV could

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induce the desorption of the oxygen molecules from the active surface of ZnONP, and

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consequently a series of ROS including hydrogen peroxide (H2O2), superoxide ions

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(O2•−) and hydroxyl radicals (OH·) were formed on the surface of ZnO nanocrystal.87,

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88

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the targeted microbes. Not only that, researchers have also begun to investigate the

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antimicrobial activity of these nanoparticles even under dark conditions.89 Till now,

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however, relatively limited amounts of data are available on nanoparticle

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antimicrobial activity in the absence of irradiation and the data on ZnONP were

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especially scarce. On the other hand, functionalization and surface treatment of these

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nanoparticles may be critical issues for high-added value applications involving

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antifungal nano-additives.90,

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should be functionalized so as to improve the stability, biocompatibility, functionality,

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sensitivity, and selectivity for various biospecies.92 Functionalization of ZnONP

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surface through direct molecule attachment or by functional groups grafted on the

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surface is considered a promising strategy for improving the overall antifungal

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activity of these nanoparticles for targeted microbes. The process of nanoparticles

The photo-induced oxidation process can cause further damage and inactivation of

91

To use these NPs in bio-applications, their surface



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functionalization by different methods (e.g. surface encapsulation, in situ synthesis,

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plasma

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characteristics has been described in many reports over the years.93-96 Recent studies

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demonstrated that ZnONP incorporated with essential oils,97, 98 polysaccharide,99, 100

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and protein-based biopolymers

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against foodborne pathogens. Therefore, the synergistic antifungal effect of ZnONP

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can be obtained by incorporating or functionalizing with bioactive substances.

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Figure 4. Mechanism of the photo-induced existence of reactive oxygen species on

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the active surface of ZnONP.

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ANTIFUNGAL MECHANISMS OF ZINC OXIDE NANOPARTICLE

technology

or

self-assembly)

101-103

for

changing

their

physicochemical

can present significant antimicrobial potential


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Antimicrobial efficiency of ZnONP has been explored in numerous studies.

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Unfortunately, inequalities in terms of synthetic approaches to NPs, inhibitory modes,

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and experimental conditions have impeded clarification on antifungal mechanism of

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ZnONP. Until now, how fungal cells sense and respond to nanoparticles associated

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with cellular physiological alterations remains unresolved. According to the existing

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information and the above-mentioned discussion, nanosized ZnO can be characterized

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by two features: one is its excellent photocatalytic property among all inorganic

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photocatalysts, and the other is the presence of zinc ions (Zn2+) in medium. Therefore,

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the photon-induced generation of ROS and a poisoning effect due to Zn2+ release are

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the two main contributors to the antifungal activity of ZnONP.

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ROS-DEPENDENT ANTIFUNGAL ACTIVITY

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The antimicrobial mechanisms of ZnONP, according to investigations by Hirota et al.

248

104

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hydrogen peroxide on the surface of ZnONP via oxygen defect sites. Oxidative stress

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generated by the production of ROS may be the major cause of NPs’ physiological

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effect, especially in the presence of illumination.106-108 In 2012, Yongsheng’s group

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reported that the photo-generated ROS kinetics were closely related to the type of

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metal oxides.109 Remarkably, they established quantitative correlations between the

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level of NPs-generated ROS and microbial survival rates. In a follow-up work,

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researchers found that the addition of nanoparticles could promote ROS production in

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a time- or dose-dependent way. 62 The application of the scavenger of ROS could

and Xu et al.,105 are generally dependent on the presence of oxygen radicals or



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conversely eliminate the antifungal performance of ZnONP. Meanwhile, a serious of

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biochemical analysis was performed by scholars in order to delineate the mechanism

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of ROS-determined inhibitory effect.60 Investigators suggested that the hyphal cell

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attempted to alleviate this ROS burden caused by ZnONP treatment through the

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enhancement of oxidative stress reactions, such as superoxide dismutase and

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ascorbate peroxidase activities. However, a higher concentration of ZnONP could

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lead to the rupture of hyphal cells and the oxidation of protein. Intensification of

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carbonyl concentration in NPs-treated fungus mediated by the production of ROS

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were clearly observed through dinitrophenylhydrazine binding assay and fourier

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transform infrared spectroscopy detection. Recently, the generation of intracellular

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ROS, induced by metal oxide nanoparticles (including ZnONP) against C. krusei, has

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been detected by Bhaskar’s group using a fluorescent dye dichlorodihydrofluorescein

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diacetate.66 They proposed that metal oxide nanoparticles could rupture the cell

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membrane thereby leading to momentous oxidative stress and yielding ROS which

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conclusively promotes DNA damage. Obviously, the appearance of ROS induced by

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ZnONP treatment should trigger other important physiological changes besides the

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above specified cellular responses. Noticeably, on the other hand, ZnONP-induced

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antifungal action should be explained by some other mechanisms. After all, oxidative

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stress driven by illumination may not be accomplished when the light source is absent

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for engineered nanoparticles.

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METAL-CONTAINING PARTICLE-MEDIATED ANTIFUNGAL EFFECT


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In previous studies, the antimicrobial action of engineered nanoparticles driven by

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oxidative stress was examined under dark conditions ascribing oxygen vacancies in

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ZnO nanocrystals.104, 105 However, there is little direct evidence for ZnONP-induced

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ROS production in biological tissues using microscopic observation and luminescent

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probes. Apparently, the mechanism for the antifungal activity of ZnONP in the

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absence of light is still somewhat unclear and remains under debate. Better

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understanding of the NP’s inhibitory performance in the dark is essential. The

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solubility of ZnO and other metallic compounds (e.g. silver and copper oxide) may be

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a pivotal parameter for physicochemical properties relevant to the antimicrobial

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efficiency of metal-containing NPs.30, 110 The most important common feature is that

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almost metal-containing NPs could be dissolved in aqueous solution to some extent.

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Hence, nanostructured ZnO are reckoned to be a limited source of zinc ions which is

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one possible reason for the fungitoxic effect of nanoparticles. 60, 109, 111, 112 Researchers

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have found that the anti-biological activity of ZnONP under dark condition was

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introduced by the toxicity of zinc ions released from metal oxide particles.74, 113 In this

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case, the property of the water-soluble and the existences of the intact particles, metal

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ions or metal complexes, became key issues for metal-containing particle-mediated

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antifungal effects. The fact that the solubility of inorganic nanoparticles depends

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largely on the testing environment and the surrounding substances has been addressed

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in a review by Casals et al.114 The most significant environmental factors influencing

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testing were water hardness, components of the complex test media and pH.115-117 For

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example, researchers have reported on the reduced solubility and toxicity of selected



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manufactured NPs toward crustaceans in natural waters.118, 119 Also, the interaction

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between NPs and the organic components in the medium, e.g. proteins, amino acids

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and some other natural organic substances, has been shown to remarkably change the

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dispersion of these metal-containing nanomaterials.30 Moreover, the solubility of the

304

aforementioned nanoparticles including ZnONP is enhanced at a more acidic pH.120,

305

121

306

NPs when antifungal tests are performed. On the other hand, whether the

307

concentration of released ions is sufficient to produce the corresponding antimicrobial

308

effects is also questioned by researchers.52,

309

discovered that though the concentration of released Zn2+ might not threat bacterial

310

growth and activity, the attachment of nanoparticles to the bacterial cell wall could in

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turn promote the antimicrobial effect of ZnONP. 105 As a result, biotoxicity effect of

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zinc ions occurred because of the local dissolution of the attached ZnONP in

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cytoplasm via occupancy competition for influx metalloprotein channels between zinc

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and other metal ions. In the study by Eue-Soon et al., there was no in-depth

315

explanation of how ZnONP attached to the cell wall dissolve or how metal ions are

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transported into the cytoplasm membrane.

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ANTIFUNGAL MOLECULAR MECHANISM

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According to the previous interpretations, the fungicidal mechanisms of ZnONP

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described as disrupting cellular structure (e.g. cell wall or membrane and organelles),

320

prohibiting biological macromolecular activity (e.g. protein, enzyme), preventing

From the above discussion, it is apparently significant to evaluate the dispersion of

105, 122-124


Recently, Eue-Soon et al.

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DNA replication, and disrupting the anti-oxidative system via a ROS and/or Zn2+

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mediated manner. However, research on the antifungal molecular mechanism of

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ZnONP has remained in its infancy. Until recently, scientists began to study the

324

molecular mechanisms explaining NPs-induced inhibitory efficiency in filamentous

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fungi.67 They endorsed the previous conclusion that oxidative stress induced by ROS

326

which is generated from NPs should be the dominant principle for the examined

327

antifungal activity. 125, 126 They further suggested that ZnONP treatment could deplete

328

glutathione (GSH) levels via the inhibition of GSH synthesizing enzymes, thereby

329

weakening the antioxidant capacity in fungal cell. As a consequence, the alterations to

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redox state and further enhancement of ROS in hyphal cell significantly upregulated

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the transcript levels of ShSOD2 and Shgst1, which are mainly responsible for

332

encoding superoxide dismutase and glutathione S-transferase. Researchers also

333

identified the genes responsible for the stress response within filamentous fungi and

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the cell uptake of nanoparticles. For instance, a zinc transporter (Shzrt1) has been

335

confirmed to be involved in cell uptake of fungitoxic nanoparticles as the over

336

expression of Shzrt1 in yeast mutants could enhance the sensitivity of fungal cells to

337

toxic metal oxides.67 Inspired by this finding, high throughput transcriptome

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sequencing of gene expression levels in mycelia cells treated with nanoparticles has

339

been conducted in our latest research (unpublished). After exposure to ZnONP,

340

changes in gene expression to varying degrees were detected in A. flavus, including

341

genes related to oxidative stress, zinc ion binding function, transmembrane transport

342

and oxidative phosphorylation functions. Furthermore, the influence of ZnONP



343

treatment on genes related to aflatoxin biosynthesis are also the focus of our

344

laboratory. Identifying their intermolecular interaction network will be benefit to

345

understand the mechanism of engineered nanoparticle antifungal activities in depth.

346

ZINC OXIDE NANOPARTICLE AS AN ANTIFUNGAL ADDITIVE IN FOOD

347

People have already developed potential applications for nanotechnology in

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practically every aspect of the food-related system; for example, as an agrichemical

349

deliver, new pesticides, nanoencapsulation of flavors or odor enhancers, anticaking,

350

UV-protection film, drinking water purification and nutritional supplements. Among

351

these applications, NPs are widely employed as an effective antimicrobial candidate

352

as part of the food matrix to prevent the growth of foodborne microbes thereby

353

improving the shelf life of products. Compared with other nanostructured particles,

354

ZnONP should exhibit more advantage due to their unique nano-properties, including

355

excellent bioavailability and self-sterilization.127 Most importantly, ZnO has been

356

reckoned as “Generally Recognized as Safe" (GRAS)” as a supplement that can

357

replenish essential zinc for human health. By analyzing the literature, the most active

358

area of development for ZnONP as a promising nano-additive is that of fabrication

359

and improvement in packaging. This may be due to the case that the public still

360

remain wary about “nanofoods” considering the uncertainty about the safety of

361

nanomaterials. Consumers are more willing to embrace nanomaterials in “out of food”

362

uses than those where NPs are directly applied to food.128, 129 As reported elsewhere,

363

one successful strategy to reinforce mechanical, barrier and structural activities of


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Page 21 of 60


364

food packaging is to incorporate ZnONP into polysaccharides, lipid and protein-based

365

biopolymers.99,

366

substrate, such a novel nanomaterial could be used as the antimicrobial agent to make

367

food matrix free from microbial contamination. By avoiding food spoilage, nanoscale

368

ZnO in packaging could slow down the oxidation rate of food components and

369

maintain product quality, including color, flavor as well as nutritional value.132, 133

370

Some researchers think that the creation of active or smart sensor systems containing

371

ZnO and other NPs could be used to detect food-relevant analytes (e.g. small organic

372

molecules, vapor or gas content and food-borne pathogens), which would be

373

revolutionary for the food industry.134-137 As a supplement, compared with other

374

sources of zinc, nano-scaled ZnO is more conducive to human absorption and has a

375

certain degree of antioxidant activity. In theory, they can be used as a nutritional

376

supplement for the production of food or health care products. However, the

377

application of nanostructed zinc oxide in the field of food additives has rarely been

378

reported, which may be related to the potential toxicity of these nanoparticles.

379

Research on the toxicity and bio-safety of NPs has become a new focus in

380

nanotechnology.

381

RISK ASSESSMENT OF ZINC OXIDE NANOPARTICLE ON HUMAN

382

HEALTH

383

Although ZnONP is a promising substitute for traditional antifungal agents in the food

384

industry, questions have been raised concerning the potential risks of human health

100, 130, 131

Once these molecules are emerged in the polymeric



Page 22 of 60

385

upon exposure to nano-sized materials, including ZnONP. In general, topically

386

engineered nanoparticles may pose systemic health threats via inhalation, skin

387

absorption, ingestion, and injection ways. Recent in vitro or in vivo studies have

388

shown the possible danger of ZnONP range from genotoxicity to reproductive toxicity,

389

as well as immunotoxicity and side effects on the nervous system of different

390

organisms and mammalian cells.138-143 Comprehensive reviews on biokinetics,144

391

particle translocation145 and toxicity mechanism146,

392

When analyzing these reports, we first noticed that the application concentration and

393

exposure conditions of ZnONP during in vivo and in vitro tests were performed under

394

acute exposure conditions with relatively high doses.138,

395

assessments may be relevant with regard to acute toxicity, but it is unclear whether

396

these engineered NPs can really be reached at such high levels in human target

397

tissues.152 In contrast, several long-term or chronic studies employing low or

398

non-toxic concentrations found that ZnONP did not pose significant danger to human

399

health.153,

400

exposure.155 Due to the different research approaches used, such these conflicting

401

documents indicate that the potential toxicity of ZnONP and other nanomaterials

402

should be interpreted with caution. Although size and shape of NPs have been proved

403

to be influential, Srivastav et al. reported that the difference in toxicity among ZnO

404

nanoparticles, micro-particles and zinc sulfate was relatively small and these particles

405

were essentially non-toxic.156 Toxicity studies on other nano-sized materials, such as

406

titanium dioxide, concluded that the toxicity performance of these nanoparticles is

154

147

have also been published.

148-151

Thus, these risk

And there has never been reported case of disease related to NPs


Page 23 of 60


407

primarily correlated with their chemical properties rather than their particle size. 157-159

408

Toxicologically, perhaps the most important focus is on the toxic mechanism of

409

nanoparticles. Although the generation of reactive oxygen species, the behavior of

410

released metal ions, and the reactions catalyzed by particle surface properties may be

411

the chief contributors to the biological toxicity of ZnONP and other nanoscale metal

412

oxides.160-164 These mechanisms of action may also be applicable to those of

413

traditional chemical substances and not a sole nano-specific toxic mechanism has

414

been determined until now.165 Overall, there is no definite evidence that ZnONP or

415

other metal-containing NPs used in industrial products pose a health hazard, but

416

instead provide obvious health benefits due to their unique physicochemical

417

properties.30,

418

inevitably raise some issues regarding food safety. Since safety data on long-term

419

adverse effects or risks of many nanomaterials are not available or are very limited, a

420

bio-safety assessment of NPs still needed and should be further explored through

421

more in vivo and in vitro studies.

422

SUMMARY AND PROSPECTIVE

423

In this review, we endeavored to give a comprehensive account of current

424

fundamental and application-driven discussions about the protective effects of

425

ZnONP against harmful fungi. We found that more progress has been made in

426

fundamental rather than translational research. Our extensive analysis was centered on

427

ZnONP due to its spectacular properties like a crystalline architecture, nanoscale

166

Expectedly, the application of NPs in food-related industries will



428

effect and photocatalytic activity. Also, the inhibitory activity of ZnONP on the

429

growth and metabolism of fungi was reviewed along with a large number of factors

430

affecting its antifungal efficacy. The improvement in the antifungal performance of

431

ZnONP was achieved by adjusting particle parameters like crystalline structure, size

432

and concentration, and even preparation method. Additionally, both illumination and

433

surface modification have been shown to improve the fungicidal performance of

434

ZnONP. Identification of these factors has led to better understanding of a growing

435

number of photogenerated ROS-mediated antifungal mechanisms. One could

436

reasonably conclude that not all of these mechanisms represent independent targets

437

(as illustrated in Figure 5). The ROS-dependent mechanism may be more dominant

438

than nanoparticles-mediated mechanism, but the latter may further influence the effect

439

of the former. Furthermore, there is not enough evidence affirming the conclusion that

440

nano-sized particles are initially more hazardous than larger particles, like

441

microparticles or bulk materials. Investigators should aim to fill the existing

442

knowledge gap in the study of toxic, genotoxic, or possible carcinogenic effect of

443

long-term treatment with ZnONP at sub-toxic doses.


Page 24 of 60

Page 25 of 60


444

Figure 5. Plausible mechanistic aspect of nanoparticles-assisted ROS-dependent

445

antifungal activity of ZnONP. Nanostructed ZnO particles could adsorb on the surface

446

of fungal cells through a specific manner and then enter into the cell by transportation

447

or endocytosis. Once nanoparticles are in contact with the cytoplasm, they can affect

448

the initial function of mitochondria and benefit the production of ROS. ROS and the

449

released Zn2+ from ZnONP may trigger many irreversible biological damages and

450

alterations in some key genes expression level.

451

The antifungal and antimycotoxigenic activities of ZnONP are generally

452

recognized nowadays and promising achievements are mentioned in the above

453

discussion. Nevertheless, there are issues that need to be clarified in order to move

454

towards the application of nanoparticle-based antifungal additives in the food industry.

455

Outstanding topics of study mainly include: (i) preparation of ZnONP to match



456

industrial needs, (ii) the difference in the inhibitory role of ZnONP on fungal growth

457

and mycotoxin production and the mechanism dictating such a difference, (iii)

458

regulation of antifungal properties via metabolism of ROS in fungal cells.

459

Additionally, mechanisms concerning the penetration, migration, accumulation and

460

biodegradation of nanoscale ZnO need further in-depth study in order to scientifically

461

and accurately evaluate the bio-safety of ZnONP. If the field can succeed in these

462

areas, then ZnONP may prove to play a vital role in many areas of the food industry

463

as a promising bioactive nano-agent.

464

ACKNOWLEDGEMENTS

465

Grants from the Science and Technology Research Program of Chongqing Municipal

466

Education Commission (Grant No. KJ 1758498); Chongqing Normal University

467

Foundation Program (Grant No. 17XL13006); the National Natural Science

468

Foundation of China (Grant No. 31671939). Sincerest thanks to the valuable

469

suggestions from Professor Changming Li (Institute for Clean Energy & Advanced

470

Materials, Faculty of Materials & Energy in Southwest University).

471

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Page 52 of 60

Table 1. Major findings in the area of ZnONP against various pathogenic fungi

Tested fungi

ZnO preparation

ZnO characteristic

Reference

Petals extract-mediated bio-synthesis

50-100 nm in diameter size

55

Candida albicans

Chitosan-linoleic acid-assisted method

Spherical shape and 30 nm in average size

56

Aspergillus flavus

Commercial purchase

A heterogeneous combination of ZnO (477

57

Trichophyton

mentagrophytes

Microsporum canis

Aspergillus fumigatus Aspergillus niger, Penicillium oxalicum, sp.,

nm) and metallic particles (7 nm) Sol-gel method

Pseudo-hexagonal shape (90-170 nm)

58

Commercial purchase

Rod-like structure and 55-85 nm in size

59

Paraconiothyrium

and

Pestalotiopsis

maculans Botrytis cinerea


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Penicillium expansum Aspergillus niger

Microwave-assisted chemical route

Spherical shape and 30-40 nm in diameter

60

Wet chemical route

Spherical and granular morphology

61

Egg white-mediated biological strategy

Spherical morphology and 10–20 nm in size

62

Wet chemical route

Spherical shape and 2-28 nm in diameter

63

Microwave-assisted chemical method

ZnONP embedded in mesoporous nanosilica

64

Chemical reduction process

76.15 nm in average size

65

Liquid phase precipitation method

40 nm in average size

66

Commercial purchase

30 nm in average diameter

67

Fusarium oxysporum Aspergillus spp. Candida albicans Fusarium sp. Aspergillus niger Fusarium oxysporum A.

alternata,

A.

niger,

B.

cinerea, F. oxysporum and P. expansum Candida krusei Sclerotinia homoeocarpa



Aspergillus flavus, Aspergillus nidulans,

Trichoderma

Leaf broth extract-mediated

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25-40 nm in diameter size

68

cerium doped flower-shaped crystal

69

bio-synthesis

harzianum, Rhizopus stolonifer Candida albicans, A.flavus

Chemical method


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Graphic for table of contents



Figure 1. Various types of nanoscale materials 280x165mm (150 x 150 DPI)


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Figure 2. Schematic representation of the scope of the current review 262x218mm (150 x 150 DPI)



Figure 3. Properties of nanostructed zinc oxide particle (ZnONP). Flower-like ZnONP as shown in inset is fabricated via a facile one-pot precipitation strategy in our laboratory. 243x204mm (150 x 150 DPI)


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Figure 4. Mechanism of the photo-induced production of reactive oxygen species on the active surface of ZnONP. 184x171mm (150 x 150 DPI)



Figure 5. Plausible mechanistic aspect of nanoparticles-assisted ROS-dependent antifungal activity of ZnONP. Nanostructed ZnO particles could adsorb on the surface of fungal cells through a specific manner and then enter into the cell by transportation or endocytosis. Once nanoparticles are inside the cytoplasm, they can interfere with energy production in mitochondria and promote the generation of ROS. ROS and zinc ions released from ZnONP may trigger many irreversible biological damages and alterations in some key genes expression level. 252x177mm (150 x 150 DPI)


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Zinc Oxide Nanoparticle as a Novel Class of Antifungal Agents

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