Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications

Rania Hamed; Ruwa Z. Obeid; Rana Abu-Huwaij

doi:10.1515/ntrev-2023-0112

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Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications

Rania Hamed , Ruwa Z. Obeid und Rana Abu-Huwaij

Veröffentlicht/Copyright: 1. September 2023

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Aus der Zeitschrift Nanotechnology Reviews Band 12 Heft 1

Abstract

Green synthesis of zinc oxide (ZnO) nanoparticles (NPs) using various plant extracts as reducing and capping agents has gained attention in recent research. The green synthesis of ZnO NPs offers several advantages such as being simple, eco-friendly, safe, cost-effective, and reproducible approach with high stability. Hence, this article provides an overview of zinc metal and ZnO compounds, and traditional chemical and physical synthesis of ZnO NPs with primary focuses on the green synthesis of ZnO NPs. This study discusses various plant extracts used and the proposed mechanisms in the green synthesis of ZnO NPs. Additionally, it explores the cytotoxic mechanisms of the green-synthesized ZnO NPs and addresses the various biomedical applications of ZnO NPs, including antibacterial, anticancer, antidiabetic, antioxidant, antifungal, antiviral, antiparasitic, anti-inflammatory, and wound healing. Moreover, the review critically discusses the toxicity of ZnO NPs and emphasizes the need for more toxicological studies to ensure the safety and facilitate the risk assessments and risk management of ZnO NPs. Furthermore, this review underlines the challenges associated with the translation process of ZnO NPs from bench to market, including the complex and time-consuming regulatory approval process for ZnO NPs, which requires a multidisciplinary approach involving scientists, regulators, and manufacturers.

Keywords: antibacterial activity; anticancer activity; antioxidant activity; antidiabetic activity; toxicity; wound healing; antifungal activity

1 Introduction

Nanotechnology is the science of design, synthesis, characterization, and development of nanomaterials [1,2]. Nanoparticles (NPs) are objects that range in size from 1 to 100 nm [3,4]. They are used to target drugs to a specific site in the body by passive or active targeting strategies, which helps reduce the side effects of drugs [5]. Presently, metal oxide NPs (MONPs) are synthesized and are used in many biomedical applications [6,7]. These MONPs include iron oxide NPs (Fe₂O₃ NPs and Fe₃O₄ NPs), magnesium oxide NPs, zinc oxide NPs (ZnO NPs), titanium dioxide NPs, and copper oxide NPs [8,9,10]. MONPs are being used in diverse fields, including medical treatments, industries like solar and oxide fuel batteries for energy storage, cosmetics and sunscreens, and in textiles [11,12].

Among other MONPs, ZnO NPs have received significant attention due to their distinct physicochemical properties and potential biomedical applications such as antibacterial, anticancer, antidiabetic, antioxidant, antifungal, antiviral, antiparasitic, anti-inflammatory, and in wound healing [13,14,15,16,17]. The characteristic properties of ZnO NPs including size, crystallinity, morphology, and chemical composition showed great potential in biomedical applications [18,19]. The nanoscale size of ZnO NPs can modify their mechanical, chemical, structural, morphological, electrical, medicinal, and optical properties [19].

Recently, the green synthesis approach has been adopted to provide biocompatible and biodegradable ZnO NPs, making them suitable for various biomedical applications [15,20]. The green synthesis approach avoids the production of unwanted or harmful by-products, offering a reliable, sustainable, and eco-friendly synthesis approach [21,22]. This approach minimizes the waste and environmental pollution resulting from toxic substances generated during the chemical synthesis process. In addition, it reduces the use of toxic solvents or chemical agents required for chemical synthesis, forming biocompatible and environmentally friendly NPs [23]. Moreover, green synthesis emerges as an inexpensive and simple approach where no sophisticated pieces of equipment are required [24]. Finally, reducing and capping agents, essential for the stabilization of the green-synthesized ZnO NPs, are obtained from natural compounds available in the plant extracts, limiting the use of toxic and expensive reagents [25,26].

The growing interest in the green synthesis of ZnO NPs, its potential applications in various fields, including biomedicine, with the intrinsic properties of the environmentally friendly nature and cost-effectiveness makes it an attractive choice to be reviewed. Therefore, this review aims to provide deep insight information of plant-mediated green synthesis of ZnO NPs recently described in the literature to clarify the unique properties of ZnO NPs that can achieve their optimal bioactivities. This article provides a comprehensive review of the synthesis methods of ZnO NPs, with a particular emphasis on green synthesis using plant extracts. The authors explore the mechanisms involved in the green synthesis of ZnO NPs, the cytotoxic mechanisms underlying their bioactivities, and a thorough discussion of their potential biomedical applications. Additionally, a concise discussion is made on the toxicological studies of green-synthesized ZnO NPs, emphasizing the need for safety, risk assessment, and risk management strategies. Moreover, the authors address the challenges associated with the translation process of ZnO NPs from basic research to successful clinical applications and commercial products, where a multidisciplinary collaboration involving scientists, regulators, and manufacturers is needed.

2 An overview of zinc and ZnO

Zinc is an essential mineral for the body and is present in the brain, bone, muscles, skin, hair, nails, and immune system [27]. Additionally, Zn is a cofactor of >300 enzymes in the body that help in the synthesis of proteins and nucleic acids, maintaining DNA replication and repair, and cell cycle progression and apoptosis [28]. Moreover, Zn plays an important role in host defense against the initiation and progression of cancer [28]. Furthermore, Zn exhibits an antioxidant activity via the catalytic action of copper/Zn peroxide dismutase, stabilizes membrane structure by competing with iron and copper which are redox active metals and protects proteins from oxidation by binding to sulfhydryl groups. Further, Zn upregulates the metal-binding protein metallothionein expression which is very rich in cysteine and is an excellent scavenger of the hydroxy free radical (·OH) [29,30,31]. Finally, Zn acts as an anti-inflammatory agent by regulating the tumor nuclear factor-kappa B (NF-κβ) transcription via the anti-inflammatory protein A20 and the receptor signaling pathway activated by peroxisome proliferator-α [31,32,33]. Deficiency in Zn may lead to the release of vitamin A from the liver due to the reduced synthesis of plasma retinol-binding protein [33,34].

ZnO has been listed by the US Food and Drug Administration as “generally recognized as safe (GRAS)” [35]. Hence, it can be used as a food additive, where Zn is considered an essential trace element that plays a vital role in the growth and development of humans and animals [35,36]. Additionally, ZnO is a II–VI semiconductor, where Zn and O are found in groups 2 and 6 on the periodic table, respectively [37]. ZnO has distinctive properties including chemical, sensing, optical, semiconducting, and electrical conductivity [38]. Moreover, ZnO is characterized by a direct wide band gap of 3.3 eV in the near UV spectrum, high exciton binding energy of 60 meV at room temperature, and a natural n-type electrical conductivity [39]. These characteristic properties make ZnO a potential material to be used for a broad range of applications in electronics, optoelectronic devices, and photocatalysis [40].

Although ZnO has a slight covalent characteristic, it has a strong ionic interaction between Zn and O with higher selectivity and heat resistance, compared with other organic/inorganic compounds. The small size of ZnO improves the Zn²⁺ dissolution rate, making it more biocompatible with normal body cells and a potential antibacterial, anti-inflammatory, and anti-tumor agent [41].

3 Chemical and physical methods for the synthesis of ZnO NPs

The multitudinous applications of ZnO NPs in various fields have raised their production. It has been reported that the global production of ZnO NPs was 570 tons/year in 2010 [42] and between 32,000 and 36,000 tons/year in 2014 [43]. Additionally, it was expected that the production would be between 1,600 and 58,000 tons/year by 2020 [42]. Yashni et al. [44] estimated the production cost of ZnO NPs (<100 nm) synthesized from orange peel extract to be 20.25 USD per kg, which was considered a cost-effective method.

Traditional chemical and physical methods have been employed in the synthesis of ZnO NPs [16,45,46]. Chemically, ZnO NPs can be synthesized by sol–gel [47,48], solvothermal [49], vapor deposition [50], co-precipitation [51], hydrothermal [52,53], thermal decomposition [54], and electrochemical reduction methods [55]. Whereas physically, ZnO NPs can be synthesized by laser ablation [56], ultrasonication [57], photoirradiation [58], ball milling [59], evaporation condensation [60], microwave-assisted combustion [61], sonochemical [62], and mechanochemical methods [63] (Figure 1). These methods have many disadvantages such as high cost, high impurities, instability, and limitations in reproducibility and reliability [64,65]. In addition, they require toxic chemicals that are hazard to the environment and medical applications [66]. Therefore, to avoid these disadvantages, alternative eco-friendly and cost-effective green methods have recently been employed to synthesize ZnO NPs [67,68,69].

Figure 1

Methods employed in the synthesis of ZnO NPs.

4 Green synthesis of ZnO NPs

The green synthesis of ZnO NPs exhibited many advantages like simplicity, eco-friendly, and biologically safe [70,71,72]. The green synthesis method reduces the need of using toxic chemicals and increases the limit to produce pure NPs [73]. By using plants or unicellular microorganisms (algae, bacteria, fungi, yeasts, and viruses) for NP synthesis (Figure 1), the addition of stabilizing agents can be reduced [74]. This is because plant phytochemicals (e.g., alkaloids, flavonoids, and polyphenols) and proteins secreted by microorganisms act as reducing and stabilizing agents which provide colloidal stability and prevent agglomeration of NPs [75,76,77]. It has been shown that plant leaves are the best source for the synthesis of metal and MO NPs. This is because the phytochemicals, especially those present in plant leaf extracts, play a dual role in reducing the metal ions and stabilizing the NPs [20,21]. Additionally, plant waste products or by-products are safe and eco-friendly because they are composed of the leftovers of natural plant extracts [21,78]. Moreover, other green resources such as egg albumin, L-alanine, and starch have been used to synthesize ZnO NPs [45]. Ijaz et al. [79] reported that the best method for the synthesis of NPs is one that is not harmful to the environment. Thus, the green method is the most preferable method. Table 1 summarizes the advantages and limitations of the chemical, physical, and green synthesis of ZnO NPs.

Table 1

Advantages and limitations of the chemical, physical, and green synthesis methods of ZnO NPs

Method	Advantages	Limitations
Chemical synthesis [80,81,82]	– Controlled size	– Use of toxic chemicals
	– High purity and quality	– Use of organic solvents
	– NPs are considerably stable	– Hazard
		– Low purity
		– Capping agents and stabilizers are required to control the size and avoid agglomeration
		– Some of the capping and stabilizing agents might be toxic
		– Irreversible pollution of the environment
Physical synthesis [82,83]	– No use of toxic ingredients	– High cost
	– High-speed method	– High energy
	– High production rates	– Low stability
	– High purity and quality	– Irreversible pollution of the environment
	– Uniform size and shape
Green synthesis [81,84,85]	– Safe and toxic free	– Difficult to control the particle size and shape
	– Simple and cost-effective	– NPs are relatively less stable
	– No expensive equipment
	– No toxic chemicals
	– Eco-friendly
	– Biocompatible
	– Energy efficient

The use of plant extracts was found to be more valuable than other biological organisms since it reduces the duration of the reactions from days to hours and prevents the risk and complicated process of preserving cell cultures [86]. The green synthesis using plant extracts provides ZnO NPs with an antibacterial effect that cannot be achieved when using physical and chemical methods. This is because the green synthesis coats the surface of the NPs with many pharmacologically active biomolecules such as flavonoids, organic acids, ketones, aldehydes, amides, quinones, or polysaccharides which enhance the ligand-based conjugation of NPs to the bacterial membrane receptor [72,87,88].

In plant-mediated-green synthesis, the use of “ideal solvents” and plant extracts (as natural resources) is essential to achieve biocompatible NPs, where the utilization of plant extracts is a rather simple and easy process to produce NPs at a large scale relative to bacteria- and/or fungi-mediated synthesis [21,89]. The “ideal solvents” such as water, carbon dioxide (CO₂), and ionic liquids such as hexafluorophosphate (PF₆) or tetrafluoroborate (BF₄) are employed in the green synthesis of MONPs [21,90]. Water is always considered an “ideal solvent” as it is the cheapest, non-toxic, non-explosive, environmentally friendly, and most available solvent [21,91]; whereas, CO₂ is a universal solvent that is available as liquid or supercritical solvent (fluid at temperature and pressure above critical point) [90]. Ionic liquids, which are composed of ions with melting points <100°C, are among the best solvents used in green synthesis. This is because ionic liquids act as reducing and protective agents, making the NP synthesis process simpler [21,90].

Although the green synthesis of ZnO NPs, using plant extracts, has attracted attention due to their broad range of applications, there has been a concern regarding their reproducibility and repeatability. This is attributed to the variation in the chemical composition of the phytochemicals of plant extracts of the same species owing to their collection from different parts of the world. This might significantly affect the reproducibility and repeatability of ZnO NPs [92]. Therefore, identifying the phytochemicals present in the plant extracts is crucial to enhance the reproducibility and repeatability of ZnO NPs. Sharma et al. [93] used ZnO NPs synthesized greenly from the seed extract of Carica papaya (C. papaya) to investigate the electrochemical sensing of silymarin molecules which decrease serum transaminases in viral hepatitis patients. The reproducibility of nanocomposite ZnO NPs was tested using three electrochemical sensors independently in 0.2 mM silymarin solution. The nanocomposite ZnO NPs showed promising reproducibility of a relative standard deviation (RSD) of 1.92% (n = 6). In addition, a repeatability of RSD of 2.31% (n = 6) was reported when the nanocomposite ZnO NPs were investigated for 0.1 mg l⁻¹ silymarin. Moreover, Muthuchamy et al. [94] fabricated glucose biosensors immobilized into ZnO NP-embedded nitrogen-doped carbon sheets for monitoring glucose. The ZnO NPs were synthesized using the peach fruit extract. The reproducibility and repeatability were determined by measuring the amperometric response against 3 mM glucose in phosphate buffer saline (PBS, pH 7). The ZnO NP biosensor showed good reproducibility (RSD = 2.99%, n = 5) and repeatability (RSD = 2.86%, n = 5).

Several factors may impact the green synthesis of ZnO NPs including temperature, pH, mixing speed, reaction time, plant extract/chemical precursor ratio, calcination temperature, and precursor concentration. These parameters may ultimately affect the shape, size, and phase of ZnO NPs [95]. It has been shown that the higher the temperature of the reaction, the smaller the size of ZnO NPs [96]. Naseer et al. [96] used a relatively high temperature of 70°C to greenly synthesize ZnO NPs from the leaf extracts of Cassia fistula (C. fistula) and Melia azedarach (M. azedarach). The average nano-size was between 68.1 and 3.62 nm, respectively. In a recent study, Jayachandran et al. [97] prepared ZnO NPs using a leaf extract of Cayratia pedata (C. pedata) at different reaction temperatures (55, 65, and 75°C). A reaction temperature of 65°C confirmed the production of ZnO NPs of 52.2 nm. Hassan Basri et al. [98] investigated the effect of the reaction temperature on the size and shape of ZnO NPs greenly synthesized using the peel extract of pineapple. When the reaction temperature was maintained at 28°C, the size of ZnO NPs was between 8 and 45 nm with a mixture of spherical and rod shapes. However, when the reaction was increased to 60°C, the size of ZnO NPs was between 73 and 123 nm with a flower rod shape.

Padalia et al. [99] demonstrated the effect of pH on the size and morphology of ZnO NPs synthesized using the leaf extract of Salvadora oleoides (S. oleoides). Based on the transmission electron microscope (TEM) analysis, ZnO NPs synthesized at pH 5 were spherical in shape with an average size of 26.6 nm, whereas, at pH 8, irregular shape ZnO NPs with an average size of 38.6 nm were formed. Additionally, ZnO NPs synthesized at pH 5 showed higher antibacterial activity against Gram-positive and Gram-negative bacteria, compared to pH 8, indicating the importance of pH on the biological activity of ZnO NPs. In another study, the effect of pH (8–14) on the green synthesis of ZnO NPs prepared from the leaf extract of Raphanus sativus var. Longipinnatus was investigated [100]. The authors showed that no UV-vis absorption peaks were observed at pH 8–10 and pH 14. At pH 12, an absorption peak was observed at 369 nm, indicating the formation of ZnO NPs with an average size of 209 nm. Mohammadi and Ghasemi [101] used different pH values (4–10), temperatures (25, 60, and 90°C), and precursor concentrations of zinc nitrate (0.005, 0.02, 0.05, and 0.3 M) to greenly synthesize ZnO NPs using the cherry leaf extract. The results showed that the size of ZnO NPs increased from 87.5 to 116 nm as the temperature increased. Additionally, the optimum synthesis conditions of pH 8, temperature 25°C, zinc nitrate concentration of 0.005 M, and incubation time of 12 h confirmed the formation of ZnO NPs with an average size of 20.2 nm and spherical morphology.

All physical features of ZnO NPs like size, morphology, and surface properties can be assessed using various characterization tools such as UV-vis spectroscopy, X-ray powder diffraction (XRPD), Fourier transform infrared (FTIR), energy-dispersive X-ray analysis, TEM, scanning electron microscopy (SEM), and dynamic light scattering [102]. Figure 2 shows the various characterization analyses of green-synthesized ZnO NPs.

$Figure 2 Characterization analyses of green-synthesized ZnO NPs including particle size distribution, differential scanning calorimetry, field emission scanning electron microscopy, X-ray diffraction (XRD), UV-vis spectroscopy (UV-vis), and FTIR [103].$

Figure 2

Characterization analyses of green-synthesized ZnO NPs including particle size distribution, differential scanning calorimetry, field emission scanning electron microscopy, X-ray diffraction (XRD), UV-vis spectroscopy (UV-vis), and FTIR [103].

5 Mechanism of green synthesis of ZnO NPs

The proposed mechanism of the green synthesis of ZnO NPs is related to the presence of phytochemicals, particularly polyphenols such as flavonoids, tannins, anthocyanidins, and phenolic acids, which act as reducing/capping agents [92,104]. The phenolic rings rich in hydroxyl groups act as chelating agents, forming complexes with Zn²⁺. A hydrolysis reaction transforms the intermediate chelated compound into zinc hydroxide Zn(OH)₂, which is then transformed into ZnO during calcination. Finally, ZnO undergoes a growth phase by electrostatic interaction, forming ZnO NPs [104,105]. Another proposed mechanism has been reported in the literature which involves the formation of ZnO NPs upon the reduction of Zn²⁺ ions, by various phytochemicals in the aqueous extract, to nanoscale zinc particles (Zn⁰) which react with dissolved oxygen to form ZnO, followed by capping with active phytochemicals to prevent agglomeration and increase the stability of ZnO NPs [105].

The redox potential of the phytochemicals is very important. It determines the extent of reduction that can occur. In the case of ZnO NP synthesis, the redox potential is usually not high enough to completely reduce Zn²⁺ ions to zerovalent Zn, resulting in the formation of ZnO NPs. The redox potential of the phytochemicals can be influenced by various factors such as the presence of functional groups, the presence of electron-donating or electron-withdrawing substituents, and the overall chemical reaction conditions (reaction time, temperature, pH, types of phytochemicals, and plant extract and metal salt concentrations) [106,107]. The other attribute is related to the stability and complexation of Zn²⁺ complexes [107]. Phytochemicals often form stable complexes with metal ions. In the case of ZnO NP synthesis, these complexes help in the stabilization of ZnO NPs by preventing their aggregation and facilitating controlled growth. The presence of functional groups in phytochemicals, such as hydroxyl (–OH), carboxyl (–COOH), or amino (–NH₂) groups, allows for the binding and complexation with Zn²⁺ ions, leading to the formation of ZnO NPs. Furthermore, the pH of the reaction medium plays a significant role in the formation of ZnO NPs. Most green synthesis methods involve alkaline conditions (pH > 7), which promote the formation of ZnO. Under these alkaline conditions, Zn(OH)₂ is formed, which subsequently reacts to produce ZnO NPs [108].

Alamdari et al. [109] describe the mechanism of the green synthesis of ZnO NPs using the Sambucus ebulus (S. ebulus) leaf extract (Figure 2). The authors proposed a reaction between flavonoid/phenolic molecules with Zn²⁺ ions via the donor–acceptor mechanism, resulting in Zn²⁺ complexes and the formation of ZnO NPs (Figure 3).

Figure 3

A schematic diagram representing the experimental work and the possible mechanism of the green synthesis of ZnO NPs using the leaf extract of S. ebulus [109].

6 Cytotoxic mechanisms of ZnO NPs

ZnO NPs are one of the most commonly used MONPs in biomedical applications as antibacterial and anticancer agents and in the cellular imaging fields [110,111,112]. The cytotoxic effect of ZnO NPs is mainly concerned with changing the cytoskeleton and nucleoskeleton of proteins and/or generating reactive oxygen species (ROS) in cells exposed to ZnO NPs [113]. Ultimately, three mechanisms are involved simultaneously in the cytotoxicity of ZnO NPs including the release of Zn²⁺, production of ROS, and direct interaction between ZnO NPs and cells [28].

6.1 Release of Zn²⁺ ions from ZnO NPs

One of the main mechanisms of ZnO NP cytotoxicity is that these NPs dissolve into free Zn²⁺ in the lysosomal acidic media, causing lysosomal destabilization, mitochondrial dysfunction, and disruption of cellular zinc homeostasis, leading to cell death [114]. The release of Zn²⁺ into the cells enables the dynamic transport of membrane, and mitochondrial and DNA damage [115]. The dissolved Zn²⁺ induced lactate dehydrogenase (LDH) leakage into the cell culture medium, which indicates cell membrane damage. Additionally, it was found that there is a significant relationship among the Zn²⁺ content, cell viability, and the LDH level [115]. Murali et al. [15] discussed the potential cytotoxicity of ZnO NPs that stems from the release of Zn²⁺ and hence their role in different biomedical applications including antibacterial, antidiabetic, antifungal, anticancer, anti-inflammatory, and antioxidant. It has been reported that Zn²⁺ is released due to the dissolution of ZnO NPs which may occur either extracellularly or intracellularly [116]. In the extracellular dissolution of ZnO NPs and due to their small size, Zn²⁺ can enter the cytoplasm via the cell membrane, inducing the production of ROS that leads to oxidative stress in many cells. However, the intracellular dissolution of ZnO NPs involves the release of Zn²⁺ due to the acidic environment of lysosomes after they were internalized by endocytosis, inducing oxidative stress and apoptosis [117]. Additionally, Zn²⁺ is one of the main contributors to the antibacterial activity of ZnO NPs, where Zn²⁺ interacts with proteins in bacteria and oxidize their amino acids, leading to protein denaturation and loss of enzyme activity. This results in the blockage of the metabolic and growth functions [118]. To summarize, the released Zn²⁺ in high levels contributed to the cytotoxicity of ZnO NPs.

6.2 Production of ROS

The second mechanism of ZnO NP cytotoxicity involves the production of ROS. When ZnO NPs enter the cells, the defense mechanism begins inside the cells, generating ROS. If the generation of ROS exceeds the limit of the antioxidant capacity of cells, ROS produces pro-inflammatory cytokines, which initiate inflammation. Inflammation induces mitochondrial disturbance that leads to an impairment in the cellular membrane, cellular components, and DNA, in addition to an increase in LDH from necrosis or apoptosis, leading to cell death [119,120]. Additionally, the generation of the intracellular ROS and the entrance of the anticancer agent into cancer cells are the main causes of destroying the electron transport chain [121]. A high amount of ROS leads to mitochondrial damage and loss in protein activity, leading to cell apoptosis [122,123,124].

In 2018, Attia et al. [125] studied the neurotoxicity of ZnO NPs when given orally to rats in different doses. They reported that ZnO NPs may reach the brain when administered orally. In addition, the exposure of cells to ZnO NPs decreases the concentration of antioxidants such as glutathione (GSH), catalase, and superoxide dismutase, where these antioxidants generally prevent or repair the damage caused by ROS and regulate the redox-sensitive signaling pathways. Thus, exposure to ZnO NPs resulted in DNA damage confirmed by increasing the percentage of DNA tail, length, and intensity. This indicates that ZnO NPs deteriorate and damage the antioxidant system via developing ROS in the brain, elevating the inflammatory response, cytokines, DNA fragmentation, and apoptosis [125]. Therefore, the green-synthesized ZnO NPs displayed oxidative stress-mediated cytotoxic effects.

6.3 Direct interaction between ZnO NPs and cells

It has been shown that there is a direct interaction between ZnO NPs and cells, resulting in a change in the cell morphology, disruption of the membrane, damage of mitochondria, and spillage of intracellular structure [126,127]. In addition, exposure to ZnO NPs changed the cellular distribution of lipid biosynthetic enzymes and the structure of the endoplasmic reticulum (ER), mitochondria, and ER–mitochondria encounter structure complex, leading to cell death [126]. Altogether, the interaction of ZnO NPs with cells caused cell death by affecting the integrity of the cell wall, homeostasis of ER, and the generation of ROS and saturated free fatty acids [126]. Yu et al. [127] showed that exposure to ZnO NPs leads to cell death via the accumulation of autophagic vacuoles and the damage of the mitochondria in normal skin cells via inducing the generation of ROS. Figure 4 illustrates the three mechanisms involved in the cytotoxicity of ZnO NPs.

Figure 4

The three mechanisms involved in the cytotoxicity of ZnO NPs: (1) direct contact with the cell membrane, (2) release of Zn²⁺, and (3) generation of ROS.

7 Biomedical applications of ZnO NPs

The use of eco-friendly, safe, inexpensive, and dexterous ways for the green synthesis of ZnO NPs has offered a revolution in various biomedical fields [111,128,129]. ZnO NPs have been employed in many life applications including drug delivery, cosmetics, medical installations (as antibacterial paints in hospitals), dentistry (for blocking microbial leakage), and orthopedics (as a reinforcing material) [35]. Recently, ZnO NPs showed promising biomedical applications such as antibacterial, anticancer, antidiabetic, antioxidant, antifungal, antiviral, and anti-inflammatory, and in wound healing [13,14,15,16]. Biomedically, several studies have proven the nontoxic effect of the surface-modified ZnO NPs, using hyaluronan, PEG, and Triton X-100, on normal human cells, without affecting the anticancer effects of ZnO NPs [111].

7.1 Antibacterial activity of ZnO NPs

The green-synthesized ZnO NPs exhibited a substantial antibacterial activity for wide-spectrum bacteria, whereby interacting with the bacterial cell surface and its core, ZnO NPs can enter inside the cells and display their bactericidal effect [130,131,132]. Therefore, the antibacterial activity of ZnO NPs revealed a promising potential to be linked with antibiotic functions, overcoming antimicrobial resistance [36]. In addition, the toxic interaction between ZnO and bacteria has proved as an antibacterial agent in the food industry [102]. This is attributed to their high specific surface area and high activity to block a wide range of pathogenic bacteria [14,133]. Recently, the antibacterial activity of ZnO NPs was proved by their ability to generate ROS such as hydroxyl radicals (·OH), hydrogen peroxide (H₂O₂), superoxide anions (O₂ · ⁻), and singlet oxygen (¹O₂). The four ROS displayed different levels of antibacterial activity. It has been shown that O₂˙⁻ and H₂O₂ exhibited lower antibacterial activity than ˙OH and ¹O₂. This is because O₂˙⁻ and H₂O₂ are less reactive and can be detoxified by endogenous antioxidants that are induced by oxidative stress. However, no enzyme can detoxify ˙OH or ¹O₂, making them more toxic [134]. Additionally, it has been reported that the negative charge of hydroxyl radicals (˙OH) and superoxide (O₂˙⁻) prevents their penetration into the bacterial cell wall. However, the direct contact between these ROS and bacterial membranes can cause bacterial death. Whereas, hydrogen peroxide (H₂O₂) can penetrate through the bacterial cell wall, getting internalized in the bacterial cell, causing cell death [104,135,136]. Additionally, the antibacterial activity involves the accumulation of ZnO NPs in the outer membrane or in the cytoplasm of the bacterial cells which triggers the release of Zn²⁺, causing disintegration of the cell membrane, damaging the membrane proteins, and instability of bacterial genomics, resulting in bacterial cell death [137,138]. Because ZnO has an amphoteric nature, it can react with acids and bases, releasing Zn²⁺ which binds to the bacterial biomolecules [139]. Figure 5 shows a schematic diagram of the antibacterial mechanisms of ZnO NPs.

Figure 5

Schematic diagram representing the antibacterial mechanisms of ZnO NPs.

Although ZnO NPs showed antibacterial activity against both Gram-positive and Gram-negative bacteria [135], the antibacterial activity of ZnO NPs depends on the sensitivity of the microorganism and the difference in the cell wall structure of Gram-positive and Gram-negative bacteria [140]. The membrane of Gram-positive bacteria is composed of a thick peptidoglycan layer (20–80 nm) that is covalently attached to teichoic, lipoteichoic acids, and surface proteins [135]. This thick layer acts as a physical barrier that protects the cells from the exterior environment, whereas the membrane of the Gram-negative bacteria is composed of a thin peptidoglycan layer (∼8 nm) and a thick lipopolysaccharide external layer (1–3 µm) [135,136].

Reddy et al. [141] reported that the minimum inhibitory concentration (MIC) of ZnO NPs (13 nm) in the Gram-positive (Staphylococcus aureus, S. aureus) and Gram-negative (Escherichia coli, E. coli) was 1 and 3.4 mg ml⁻¹, respectively. This indicates that the inhibition of Gram-positive bacteria required a lower concentration of ZnO NPs than the Gram-negative bacteria. This was attributed to the fact that the peptidoglycan layer of S. aureus can promote the attack of ZnO NPs inside the cell, whereas the cell wall components of E. coli, particularly lipopolysaccharides, can impede this attack [135]. Similar results were reported by Tayel et al. [142], who studied the antibacterial activity of ZnO powder and ZnO NPs against nine bacterial strains. The study showed that ZnO NPs were more efficient as antibacterial agents than the powder and that Gram-positive bacteria were more sensitive to ZnO NPs than Gram-negative bacteria. Contrarily, Shinde et al. [140] showed that the antibacterial activity of ZnO microspheres against S. aureus was lower than E. coli. Researchers suggested that the difference in the cell wall structure of Gram-positive and Gram-negative bacteria is responsible for this outcome, where the thick peptidoglycan layer of S. aureus acts as a physical barrier, preventing the penetration of ZnO NPs through the cell wall. However, the thinner peptidoglycan layer of E. coli allows the penetration of ZnO NPs, rupturing the cell wall [140].

Moreover, d’Agua et al. [143] evaluated the antibacterial activity of ZnO NPs containing cotton fibers against Gram-positive bacteria (S. aureus, S. epidermidis, and Propionibacterium acnes [P. acnes]) and Gram-negative bacteria (E. coli and Pseudomonas aeruginosa [P. aeruginosa]). The agar diffusion and absorption methods were used in the study. The results showed that ZnO NPs containing cotton fibers exhibited higher antibacterial activity against Gram-positive bacteria than Gram-negative bacteria. The lower sensitivity of ZnO NPs toward Gram-negative bacteria can be attributed to the complex structure of the bacterial cell wall, where the thick outer lipopolysaccharide membrane surrounds the thin peptidoglycan layer and acts as a barrier, protecting against ZnO NPs. The authors reported that the antimicrobial studies of ZnO NPs against Gram-positive and Gram-negative bacteria showed contradictory results, where some studies have shown a stronger antibacterial effect of ZnO NPs on Gram-positive bacteria, whereas other studies have shown that Gram-negative bacteria are more sensitive to ZnO NPs [143].

Jiang et al. [144] studied the interaction between ZnO NPs and the Gram-negative bacteria E. coli to examine the antibacterial mechanism of ZnO NPs. It was found that using ZnO NPs (30 nm) and the direct contact between ZnO NPs and the phospholipids bilayer of E. coli membrane led to a disruption in the E. coli membrane, measured by quantifying the leakage of the intracellular K⁺ from the bacterial membrane, causing cell death. Although mannitol, vitamin E, and GSH were used as radical scavengers to quench the release of ROS generated from ZnO NPs and thereby suppress their antibacterial activity, the antibacterial activity of ZnO NPs against E. coli indicates the generation of ROS, particularly the (·OH) radicals.

Agarwal et al. [102] reviewed the mechanism of the antibacterial activity of the green-synthesized ZnO NPs. The results showed that ZnO NPs, due to their large surface area to volume ratio, can bind to the bacterial cell surface via a large number of ligand binding sites like proteins, lipids, phospholipids, and lipoteichoic acid. Additionally, the authors reported that Gram-negative bacteria have less resistance to ZnO NPs due to their thin layer of peptidoglycan, making ZnO NPs more toxic to this type of bacterium. The antibacterial mechanisms of ZnO NPs involve the disruption of cell membranes, release of Zn²⁺ resulting in ROS generation, DNA disruption, protein oxidation, lipid peroxidation, and metabolic enzyme inhibition which blocks food or respiratory pathways, causing cell death.

The cytotoxicity of ZnO NPs depends on different parameters of NPs such as size, shape, surface charge, and concentration. In addition, the pH and temperature of the culture medium impact the antibacterial activity of ZnO NPs, where the acidic pH from 4 to 5 and high temperatures increased the antibacterial activity of ZnO NPs. This is because acidic media enhanced the dissolution rate of ZnO NPs, hence increasing the concentration of Zn²⁺ in the media and improving the activity against the microorganisms [102,145]; however, high temperatures enhanced the production of ROS [146,147].

Several studies have confirmed the relationship between the size and morphology of ZnO NPs and their antibacterial activities [104,118,148]. Recently, Sharma et al. [148] studied the antibacterial activity of different sizes and shapes of ZnO NPs, prepared from the plant extract of Aloe vera. The size of ZnO NPs ranged between 40 and 180 nm with hexagonal, spherical, cylindrical, and cuboidal shapes. The cuboidal ZnO NPs exhibited higher antibacterial activity against S. aureus, B. subtilis, and E. coli, compared to the spherical and hexagonal ZnO NPs. Another study by Álvarez-Chimal et al. [118] investigated the effect of the size of the green-synthesized ZnO NPs (7–130 nm), prepared from the Dysphania ambrosioides (D. ambrosioides) extract, on the antibacterial activity against various pathogenic bacteria. It was found that the smaller the size of ZnO NPs (4–10 nm), the higher the antibacterial potential, particularly against S. aureus and E. coli. A very recent study by Fouda et al. [104] demonstrated the high antimicrobial potential of spherical ZnO NPs (10–45 nm), prepared from the peel aqueous extract of Punica granatum (P. granatum), against Gram-positive and Gram-negative bacteria, and unicellular fungi with an MIC of 12.5–6.25 µg ml⁻¹. The authors attributed the high antimicrobial potential to the high generation of ROS when pathogenic microbes are treated with smaller sizes of ZnO NPs.

Additionally, it has been shown that the interaction between NPs and bacterial membranes is influenced by the shape of NPs, where the triangular-shaped NPs showed better interaction with cell membranes than the rod or spherical ones, enhancing the antibacterial effect [102]. Moreover, the shape of ZnO NPs affects the release of Zn^2+, where the shape influences the surface area of NPs and hence their solubility [102]. For instance, it has been shown that the spherical-shaped ZnO NPs showed better solubility and higher Zn²⁺ release than the rod-shaped ones [149].

The surface charge of ZnO NPs is one of the important parameters that determine their antibacterial activity, where a correlation was established between the zeta potential of NPs, the surface charge of bacterial cells, and the antibacterial activity [150,151]. For instance, Mendes et al. [152] stated that the positively charged ZnO NPs showed better binding toward the negatively charged surface cell membrane via electrostatic interactions, improving the toxicity of NPs against Gram-positive and Gram-negative bacteria. Teichoic acid in the peptidoglycan layer and lipoteichoic acid in the membrane, responsible for the negative charge of the bacterial cell membrane, act as chelating agents for Zn²⁺ which is carried by passive diffusion across membrane proteins [152].

Thi et al. [153] reported the synthesis of spherical ZnO NPs (20 nm) from the orange fruit peel extract and zinc acetate dihydrate which were used as a reducing agent and a chemical precursor, respectively. The antibacterial activity of ZnO NPs was studied against E. coli and S. aureus. The results showed a strong bactericidal effect of >99.9% against E. coli and 89.4–98.1% against S. aureus at an NP concentration of 0.025 mg ml⁻¹ and 8 h of incubation. Additionally, the mechanism of the bactericidal activity of ZnO NPs was based on the generation of ROS and their interaction with cell membranes, resulting in DNA and cell wall damage. In the same year, Umavathi et al. [154] synthesized green spherical ZnO NPs from the Parthenium hysterophorus (P. hysterophorus) leaf extract by a single-step process. ZnO NPs were characterized by UV-Vis spectroscopy and FTIR to confirm the presence of flavonoids, phenolics, tannins, phytic acid, and ZnO, whereas the TEM and SEM micrographs revealed the spherical shape and the nanosized range of 10 nm of ZnO NPs. The XRPD results confirmed the formation of the hexagonal wurtzite structure. ZnO NPs exhibited strong antibacterial activity against Gram-positive and Gram-negative organisms and fungal strains with a concentration-dependent effect. For instance, it was found that 10 mg of ZnO NPs was sufficient to exhibit a maximum inhibitory concentration against E. coli. Moreover, Safavinia et al. [155] used Daphne oleoides (D. oleoides) leaf extract, which contains five polyphenolic compounds, to prepare ZnO NPs and embed them into silica gel (SG) matrix, forming ZnO/SG nanocomposites. The antibacterial activity of ZnO/SG nanocomposites was evaluated against pathogenic bacteria and compared with the unembedded ZnO NPs. Data showed that ZnO NPs were stabilized by the SG matrix which prevents their agglomeration. Additionally, the surface area of ZnO/SG nanocomposites was higher than the unembedded ZnO NPs, demonstrating greater antibacterial activity against pathogens than the unembedded ZnO NPs.

The antibacterial activity of green-synthesized ZnO NPs was compared to their chemical counterparts. Gunalan et al. [133] found that the antimicrobial activity of green-synthesized ZnO NPs (40 nm), prepared from aloe leaf extract, was higher than that of the chemical ZnO NPs (25 nm). The antimicrobial activity was tested against different types of bacteria and fungi at various concentrations. In another study [156], the antibacterial activity of ZnO NPs, prepared from the leaf extract of Sesbania grandiflora (S. grandiflora), was compared to that of the chemical ZnO NPs, prepared by the co-precipitation method. The study showed that the green-synthesized ZnO NPs exhibited higher antibacterial activity against Gram-positive (S. aureus) and Gram-negative (P. aeruginosa) bacteria, in agreement with Gunalan et al. [133]. Similarly, a recent study by Bekele et al. [157] compared the antibacterial activity of the green (11–21 nm) and chemically synthesized (30–40 nm) ZnO NPs against Bacillus subtilis (B. subtilis), S. aureus, and Salmonella typhimurium (S. typhimurium). The green and chemical ZnO NPs showed a strong antibacterial activity with zones of inhibition of 15–24 and 7–15 mm, respectively, suggesting that the green-synthesized ZnO NPs showed promising antibacterial activity.

7.2 Anticancer activity of ZnO NPs

Scientists are putting a lot of effort to develop effective treatments to kill cancer cells with minimum side effects. Nowadays, numerous studies have been performed to advance the use of green-synthesized ZnO NPs to treat different types of cancers [158,159,160]. The role of ZnO NPs involves the anticancer activity on different types of cancers and targeted drug delivery by using ZnO NPs as nanocarriers for chemotherapeutic drugs.

7.2.1 Role of ZnO NPs in anticancer activity

ZnO NPs cause oxidative stress in cancer cells, leading to their damage, due to the rapid dissolution of ZnO NPs into Zn²⁺ at acidic pH [70]. The low endosomal pH of 6.3, 5.5, and 4.7 in the early endosome, late endosome, and endosome, respectively, induce the release of soluble Zn^2+, causing lysosomal destabilization and cell death [28]. The higher selectivity of ZnO NPs toward cancer cells, compared to normal cells, is attributed to the electrostatic interaction between the positively charged ZnO NPs, under physiological conditions, and the anionic phospholipids on the outer membrane of cancer cells which are present at high concentration. This interaction increases the cellular uptake of ZnO NPs by cancer cells and hence their cytotoxicity [161]. Hanley et al. [162] showed that ZnO NPs have 28–35 times more selective cytotoxicity against cancer cells compared to normal cells. Additionally, they reported that altering the surface properties of ZnO NPs may further enhance their cytotoxicity against cancer cells [162]. Moreover, cancer cells possess higher levels of ROS, owing to their rapid metabolism, when compared to normal cells. Hence, when cancer cells are treated with ZnO NPs, more ROS are produced, resulting in severe oxidative stress that promotes cell death [28,161]. Finally, the enhanced permeation and retention effect in cancer cells to ZnO NPs, due to their small size and surface properties, enhances the cytotoxicity of ZnO NPs against cancer cells compared to normal cells [28].

Sharmila et al. [163] used the Tecoma castanifolia (T. castanifolia) leaf extract for the green synthesis of spherical ZnO NPs (70–75 nm) to evaluate their anticancer activity against lung cancer. The results demonstrated that ZnO NPs exhibited antibacterial, antioxidant, and anticancer activities. Additionally, it was found that an increase in the ZnO NP concentration proportionally increases the radical scavenging activity. ZnO NPs exhibited an anticancer activity with half-maximal inhibitory concentration (IC₅₀) around 65 µg ml⁻¹, confirmed by the cytotoxic effect on the proliferation of human lung carcinoma (A549) cells, tested by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Thus, ZnO NPs can be used as nano-delivery systems in various biomedical applications. Ruangtong et al. [164] used banana peel crude extract as a reducing and capping agent and zinc acetate as a chemical precursor to synthesize ZnO NPs with rod-like or sheet-like structure, where the shape of NPs was varied based on the crude extract concentration used in the reaction. The ZnO NPs and nanosheets were investigated for their antibacterial and anticancer activities against skin, colorectal, and liver cancers. The ZnO nanosheets inhibited the growth of Gram-negative (E. coli) and Gram-positive B. subtilis and Staphylococcus epidermidis (S. epidermidis) bacteria. In addition, ZnO nanosheets demonstrated potent anticancer activity against colorectal (SW620), skin (A431), and liver cancer cells (HepG2) without affecting the normal cells. Similarly, Jevapatarakul et al. [165] synthesized green ZnO NPs (200 nm) and nanosheets (500 nm) from the crude extract of Cratoxylum formosum (C. formosum) leaves to assess their anticancer activity against non-melanoma skin cancer cells. The shape of ZnO NPs varied based on the concentration of the crude extract and the synthesis process. The cytotoxic activity of ZnO NPs nanosheets was evaluated by testing the cell viability on epidermoid carcinoma cell line (A431), normal kidney fibroblasts (Vero), and liver cancer cells (HepG2). ZnO NPs at 120 µg ml⁻¹ concentration significantly inhibited the cell viability of A431 cells without affecting Vero cells. Contrarily, a higher concentration of ZnO NPs (300 µg ml⁻¹) showed a weak cytotoxic activity when applied to the HepG2 liver cell line. The ZnO NPs nanosheets showed greater cytotoxicity against A431 cells when compared to the spherical ZnO NPs (∼200 nm). Additionally, the spherical ZnO NP nanosheets inhibited the growth of E. coli, B. subtilis, and S. epidermidis. Moreover, ZnO NP nanosheets altered several transcript pathways responding to the generation of ROS and hydrogen peroxides that are involved in the cytotoxic effect on A431, causing cell death due to oxidative stress and inflammatory response [165].

Naser et al. [72] synthesized ZnO NPs using the root hair extract of Phoenix dactylifera (P. dactylifera) and 0.6 M zinc acetate dihydrate to assess their anticancer activity against lung and breast cancers. The spherical ZnO NPs (31–48 nm) were 45% more cytotoxic than doxorubicin (DOX) hydrochloride alone. The ZnO NPs proved their cytotoxic efficacy by reducing the cell viability of the triple negative breast cancer cell line (TNBC) to 9.0% and showed 82.3% cytotoxic efficacy against lung cancer cell line (A549), confirming that ZnO NPs exhibited a potent anticancer activity. Moreover, ZnO NPs showed higher antibacterial activity against various microorganisms than those of penicillin, gentamycin, and tetracycline. A follow-up study conducted by the same research group evaluated the loading of these ZnO NPs into transdermal patches for breast cancer therapy [71]. Patches were prepared from the film-forming polymer Carbopol, backing layer ethylene-vinyl acetate, and ZnO NPs (88 nm) with a zeta potential of −16.63 mV. Patches were clear, transparent, and flexible with uniform thickness and weight of 0.25 mm and 0.42 g, respectively, and a surface pH of 6.25. The content of ZnO NPs in the patches was 91.7–94.4%. In addition, ZnO NPs from patches exhibited a sustained release profile over 25 h. Moreover, the cytotoxic effect of ZnO NPs against the TNBC cell line was dose-dependent ranging from 0.16 to 2.5 µg ml⁻¹ with IC₅₀ of 0.42 µg ml⁻¹, significantly lower than the IC₅₀ of DOX (4.58 µg ml⁻¹) (p < 0.05). Whereas the IC₅₀ on human dermal fibroblast (HDF) was 1.61 µg ml⁻¹, demonstrating a stronger effect of ZnO NPs in inhibiting the growth of cancerous cells, compared to that of DOX. Thus, ZnO NP-loaded patches may offer a potential transdermal delivery platform for breast cancer treatment by overcoming the limitations of invasive chemotherapy delivery.

In 2020, Duan et al. [166] synthesized ZnO NPs from Cardiospermum halicacabum (C. halicacabum) using an eco-friendly green method. The spherical shape of ZnO NPs (10–20 nm) was determined by TEM and evaluated against skin melanoma. The antitumor activity and apoptosis for the prepared ZnO NPs were explored using a human melanoma cell line (A375). The ZnO NPs exhibited cytotoxic activity against cancer cells. In addition, the exposure to ZnO NPs resulted in an elevation in the ROS level and apoptotic markers (caspases 3, 8, and 9) and stimulation of apoptotic cell necrosis in the tumor cells. Furthermore, Selim et al. [167] synthesized ZnO NPs from the aerial part of Deverra tortuosa (D. tortuosa) to examine their anticancer activity against colorectal and lung cancers that are associated with the greatest mortality. The plant was collected from a natural ecosystem in Egypt. The resulting ZnO NPs (15.2 nm) showed selective cytotoxic activity against two cancer cell lines, the human lung cancer cell line (A594) and the human colon cancer cell line (Caco-2), providing a safer alternative platform to conventional cancer therapy.

The research on the green synthesis of ZnO NPs has been continued. Recently, Vakayil et al. [168] synthesized ZnO NPs from rhizomes of the Acorus calamus (A. calamus) to examine their cytotoxic effect against skin cancer. The ZnO NPs were then coated with cotton fabrics to reduce skin infections. The cotton-coated ZnO NPs showed a cytotoxic and antiproliferative activity against the SK-MEL-3 skin cancer cell line which was proved by the morphological changes in cells such as shrinkage, rounding, irregular shape, and detachment in cancer cells. In addition, the MTT assay test showed a suppression in cell viability against the SK-MEL-3 cell line with an IC₅₀ value of 17.50 µg ml⁻¹ of the coated ZnO NPs. Finally, the cotton-coated ZnO NPs efficiently inhibited the growth of bacteria, demonstrating a potential antibacterial activity. Thus, the cotton-coated ZnO NPs could be utilized in the medical field in the future.

A recent study by Chandrasekaran et al. [169] compared the anticancer activity of ZnO NPs, prepared by green and chemical methods, against the MCF-7 breast cancer cell line. The green-synthesized ZnO NPs were prepared using the Vinca rosea (V. rosea) leaf extract, whereas chemical ZnO NPs were prepared by the precipitation method. The results showed that the anticancer activity of the green-synthesized ZnO NPs (16–41 nm) with spherical shape was higher compared to chemically synthesized counterparts [169].

7.2.2 Role of ZnO NPs in targeted drug delivery

The combination between ZnO NPs and the chemotherapeutic agents demonstrated a potential effect in treating cancer. George et al. [170] studied the therapeutic effect of quercetin (QE), extracted from onion peel waste and formulated as chitosan hydrogel. Using melon seeds, the QE hydrogel matrix was loaded with green-synthesized ZnO NPs forming QE-loaded nanohybrid hydrogels. The release of QE from the hydrogels was the highest in an acidic environment (pH 5), thus suitable for anticancer applications. The growth of S. aureus and Trichophyton rubrum (T. rubrum) strains was inhibited by the commercial QE and QE-loaded nanohybrid hydrogels. The cytotoxicity and anticancer activity of QE-loaded nanohybrid hydrogels were studied against skin cancer using normal murine fibroblast cells (L929) and human dermal carcinoma cell lines (A431), respectively. It was found that the QE-loaded nanohybrid hydrogels were biocompatible toward healthy cells and exhibited enhanced anticancer activity toward A431, compared to commercial QE. The kinetic drug release mechanism followed Fickian diffusion. This suggests that the combination of ZnO NPs and QE in the QE-loaded nanohybrid hydrogels showed synergistic antibacterial and anticancer activities via enhancing the cellular uptake of QE, highlighting their potential applications in the biomedical fields. Recently, Chelladurai et al. [171] synthesized amine-functionalized ZnO NPs that were covalently linked to mupirocin using an organosilane linker. Mupirocin is a crotonic acid derivative extracted from Pseudomonas fluorescens (P. fluorescens) used to treat superficial skin infections like impetigo and microbial infections caused by Gram-positive and Gram-negative bacteria. The ZnO NPs were green synthesized from the Alpinia calcarata (A. calcarata) rhizome extract. The effect of mupirocin-loaded ZnO NPs on skin cancer and skin infection was investigated. The green spherical ZnO NPs (19 nm) exhibited a crystallite grain size of 24.75 nm. The conjugated NPs showed a strong antiproliferative effect of 63% on human epidermoid carcinoma cells (A431), providing a new nanotechnology platform for skin cancer therapy. Moreover, mupirocin-loaded ZnO NPs demonstrated potency as antioxidant agents and significantly inhibited the growth of Vibrio cholerae (V. cholerae), Enterococcus faecalis (E. faecalis), and Listeria monocytogenes (L. monocytogenes).

Additionally, it has been shown that the biocompatibility and biomedical activity of coated and embedded ZnO NPs were further improved compared to their uncoated and unembedded counterparts [155,172]. For instance, Batool et al. [172] greenly synthesized ZnO NPs (20–40 nm) using the Aloe barbadensis (A. barbadensis) leaf extract. The ZnO NPs were loaded with the chemotherapeutic agents, doxorubicin (DOX) and gemcitabine (GEM), and were studied for their antitumor cytotoxic activity against breast cancer (the leading cause of cancer death among females), surface-PEGylation, and drug loading capacity. PEGylated ZnO NPs (PEG-ZnO NPs) and their non-PEGylated counterparts (ZnO NPs) showed higher DOX loading capacity and encapsulation efficiency compared to GEM. In addition, DOX/PEG-ZnO NPs and DOX/ZnO NPs exhibited significant anticancer activity against TNBC, with DOX/PEG-ZnO NPs showing greater anticancer activity. The loading of DOX into green-synthesized ZnO NPs has been investigated by Vimala et al. [173], who used the palm fruit extract Borassus flabellifer (B. flabellifer) to treat breast and colon carcinoma. The results proved that DOX/ZnO NPs exhibited high efficacy against breast and colon cancer, and thus are considered a promising drug delivery system. Therefore, plant-mediated green-synthesized ZnO NPs could have huge applications in cancer treatment and thus become a major area of research.

Finally, the anticancer potential of different parts of a plant might vary based on the specific plant species and the phytochemicals present in those parts. Because it is difficult to make a general statement about which part of plants consistently shows the best anticancer potential, different parts of plants have been studied extensively for their anticancer activity. Leaves, roots, stems, flowers, and even certain fruits of various plants have demonstrated anticancer activity [174]. It is important to note that the presence and concentration of phytochemicals might vary among different plant parts. Additionally, the extraction methods used to obtain these compounds can affect their potency. In some cases, leaves have been found to possess high levels of phytochemicals such as polyphenols, flavonoids, and alkaloids, which exhibit anticancer activity [175]. Leaves are often rich in phytochemicals due to their primary role in photosynthesis [176]. However, this does not necessarily mean that leaves always show the best anticancer potential compared to other plant parts. Contrarily, the roots of certain plants have also been extensively studied for their anticancer activity [177,178]. Roots may contain a range of phytochemicals such as alkaloids, terpenoids, and polysaccharides, which contribute to their therapeutic potential [179]. Ultimately, the choice of the plant part to be investigated for its anticancer potential depends on the specific plant species, desired phytochemicals, and traditional or scientific knowledge about the plant’s medicinal properties. Further research is still necessary to compare the effectiveness of different plant parts and their phytochemicals in combating cancer cells.

In the context of anticancer applications, the association of phytochemicals with ZnO NPs can enhance their cytotoxic activity against cancer cells [20,180]. Phytochemicals, such as polyphenols and flavonoids, have shown anticancer activity on their own [181]. When attached to the surface of ZnO NPs, these compounds can potentially exert synergistic effects, leading to increased cytotoxicity against cancer cells [182]. For example, a study by Gobinath et al. [183] demonstrated that the metabolites present in the leaf extract of Calotropis gigantea (C. gigantea) enhanced the cytotoxicity of ZnO NPs against human breast, cervical, and hepatic cancer cells.

7.3 Antidiabetic activity of ZnO NPs

Zinc is a vital key factor in the glucose metabolic process which improves hepatic glycogenesis [184]. In addition, Zn reduces gluconeogenesis and glycogenolysis processes by inhibiting glucagon excretion [185]. Rajakumar et al. [186] used the leaf extract of Andrographis paniculata (A. paniculata) as a reducing and capping agent to synthesize ZnO NPs and study their antioxidant, antidiabetic, and anti-inflammatory activities. The antidiabetic activity was investigated by evaluating the α-amylase inhibitor activity. The proteins, polyphenols, alkaloids carboxylic acids, and flavonoids in the leaf extract, which contained free amino acids and carboxylic groups in their structures, influenced the formation of ZnO NPs by interacting with Zn²⁺. The FTIR results demonstrated the role of the phenolics, terpenoids, and proteins of the A. paniculata leaf extract in the synthesis and stabilization of ZnO NPs. The XRPD pattern revealed that ZnO NPs were in the form of nanocrystals. The ZnO NPs were spherical (96–115 nm) and hexagonal (57 ± 0.3 nm) in shape, as corroborated by SEM and TEM studies, respectively. The results of the antioxidant, antidiabetic, and anti-inflammatory studies showed that ZnO NPs can decrease the sugar level and inflammations, possessing strong biological activities which could be utilized in pharmaceutical and biomedical applications.

Argade et al. [187] used the Albizzia lebbeck (A. lebbeck) aqueous bark extract for the synthesis of ZnO NPs. The ZnO NPs were evaluated for antidiabetic activity in vitro using the α-amylase inhibitor activity and glucose uptake by yeast cells. The α-amylase inhibitory activities by the A. lebbeck bark extract, ZnO NPs, and the antidiabetic drug Acarbose (used as a control) were found to be 73.3, 54.7, and 46.7%, respectively. The IC₅₀ of the α-amylase activity of the A. lebbeck bark extract, ZnO NPs, and Acarbose were 4.9, 9.6, and 3.9 µg ml⁻¹, respectively. The data demonstrated that Acarbose exhibited effective antidiabetic activity compared with the plant bark extract and ZnO NPs. In addition, the glucose uptake by yeast cells showed a dose-dependent manner which was directly proportional to the sample concentration. The ZnO NPs at 1 µg ml⁻¹ concentration enhanced the glucose uptake by 89.2%, thus higher than that of the plant bark extract and the antidiabetic drug metformin (used as a control) of 62.5 and 94.2%, respectively, at the same concentration. Additionally, ZnO NPs were evaluated in vitro for their antioxidant activity using the reducing power ability and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay tests. The ZnO NPs showed powerful DPPH scavenging activity of 66.7% and IC₅₀ of 7.0 µg ml⁻¹. Moreover, the results revealed that ascorbic acid (used as a control) exhibited higher reducing power ability compared to the bark extract and ZnO NPs. Taking together, the results of these studies demonstrated that the green-synthesized ZnO NPs acted as a potent antidiabetic agent as evidenced by the decreasing glucose level.

7.4 Antioxidant activity of ZnO NPs

One of the promising biomedical applications for ZnO NPs is their antioxidant activity [15]. The antioxidant activity of ZnO NPs can be determined by the DPPH assay method. This method is associated with a change in the color of the DPPH methanolic solution from deep violet to a stable pale yellow, upon the addition of ZnO NPs. This indicates the scavenging activity of ZnO NPs by donating an electron from the oxygen atom to the odd electron of the nitrogen atom, resulting in the formation of a stable DPPH molecule [15,188].

Suresh et al. [189] synthesized ZnO NPs using Artocarpus gomezianus (A. gomezianus). ZnO NPs showed substantial antioxidant activity against DPPH free radicals with IC₅₀ of 10.8 mg ml⁻¹. The same research group synthesized green ZnO NPs using the aqueous plant extract of C. fistula, employing the solution combustion method [190]. The results showed that ZnO NPs exhibited a potential antioxidant activity with IC₅₀ of 2.8 mg ml⁻¹ via scavenging DPPH free radicals [190]. Nagajyothi et al. [191] evaluated the antioxidant activity of ZnO NPs, prepared from the root extract of Polygala tenuifolia (P. tenuifolia), using DPPH free radical assay. The results showed that ZnO NPs established moderate antioxidant activity by scavenging 45.5% DPPH at 1 mg ml⁻¹. Siripireddy et al. [192] used the Eucalyptus globulus (E. globulus) leaf extract to synthesize spherical ZnO NPs (12 nm) under ambient conditions. ZnO NPs possessed antioxidant activity of 82% scavenging potential against DPPH, compared to ascorbic acid (used as a reference) with IC₅₀ of 46.6 µg ml⁻¹. In another study [85], ZnO NPs were green-synthesized using the aqueous stem extract of Ruta graveolens (L.) (R. graveolens L). The results showed that ZnO NPs (28 nm) possessed DPPH free radical scavenging activity with IC₅₀ of 9.3 mg ml⁻¹. Additionally, the antioxidant activity of ZnO NPs, prepared from the leaf extract of Ceropegia candelabrum (C. candelabrum), showed DPPH free radical scavenging activity ranging from 0 to 55% with IC₅₀ of 95.1 µg ml⁻¹, compared to 75% inhibition by ascorbic acid (used a positive control) at 50 µg ml⁻¹ [193]. Moreover, it was found that the antioxidant activity increased with an increase in the ZnO NP concentration. Khan et al. [194] investigated the antioxidant activity of ZnO NPs, prepared from the Trianthema portulacastrum (T. portulacastrum), using the DPPH assay method. The authors reported that the antioxidant activity of ZnO NPs is attributed to the small size, large surface area, surface charge density, and capping materials present on the surface of ZnO NPs. Additionally, it was found that the free radical inhibition of ZnO NPs was concentration-dependent [194]. Alamdari et al. [109] revealed that ZnO NPs (17 nm), green-synthesized from the leaf extract of S. ebulus, exhibited H₂O₂ free radical scavenging activity with IC₅₀ of 43 µg ml⁻¹. The researchers reported that the presence of Zn²⁺ could enhance the antioxidant activity of ZnO NPs. Recently, Faisal et al. [195] green-synthesized ZnO NPs (66 nm) from the aqueous fruit extract of Myristica fragrans (M. fragrans). The antioxidant activity of ZnO NPs was proved using four assay methods (total antioxidant capacity, total reduction power, 2,2′-azino-bis(3-ethylbenzothiazoline 6-sulfonic acid), and DPPH free radical scavenging assay. In another recent study, Abdelbaky et al. [26] demonstrated the antioxidant activity of ZnO NPs, prepared from Pelargonium odoratissimum (L.) (P. odoratissimum L.) with IC₅₀ of 28.1 µg ml⁻¹. Therefore, the results of these studies revealed that the green-synthesized ZnO NPs possessed antioxidant activity by scavenging DPPH free radicals.

7.5 Antifungal activity of ZnO NPs

In addition to the aforementioned biomedical applications, the green-synthesized ZnO NPs demonstrated a potential antifungal activity toward several types of fungi [15,74,135]. The antifungal mechanism was described by the ability of ZnO NPs to enter the fungal membrane by diffusion and endocytosis. In the cytoplasm, ZnO NPs interfere with the mitochondrial function, initiating the production of ROS and the release of Zn²⁺. The overproduction of ROS and Zn²⁺ resulted in irreversible DNA damage and cell death [15,135]. Padalia and Chanda [196] reported the green synthesis of ZnO NPs (17.3 nm) using the leaf extract of Ziziphus nummularia (Z. nummularia). ZnO NPs showed higher antifungal activity against Candida albicans (C. albicans) than the azole antifungal agents. Miri et al. [197] used Prosopis farcta (P. farcta) to synthesize ZnO NPs (40–80 nm) and investigated their antifungal activity against C. albicans with MIC of 128 µg ml⁻¹ and minimal fungicidal concentration (MFC) of 256 µg ml⁻¹. Recently, Yassin et al. [198] studied the antifungal activity of ZnO NPs (22.8 nm) synthesized greenly from the peel extract of pomegranate. The antifungal activity of ZnO NPs was tested against three types of candida strains, C. albicans, C. tropicalis, and C. glabrata. A 100 µg of ZnO NPs per disk demonstrated antifungal activity against C. albicans, C. tropicalis, and C. glabrata, with zones of inhibition of 24.18, 20.17, and 26.35 mm, respectively. The MIC and MFC of ZnO NPs against C. tropicalis were 10 and 20 μg ml⁻¹, respectively. Further, ZnO NPs demonstrated a synergistic efficiency against C. albicans with the antifungal drugs fluconazole, nystatin, and clotrimazole; whereas terbinafine, nystatin, and itraconazole showed a potential synergism against C. glabrata with ZnO NPs.

Additionally, the green-synthesized ZnO NPs exhibit antifungal activity against plant pathogenic fungi [199,200]. Jamdagni et al. [201] synthesized ZnO NPs using the Nyctanthes arbortristis (N. arbortristis) flower extract. The ZnO NPs (12–32 nm) were tested against five phytopathogens Alternaria alternata (A. alternata), Fusarium oxysporum (F. oxysporum), Aspergillus niger (A. niger), Penicillium expansum (P. expansum), and Botrytis cinerea (B. cinerea), which showed MICs of 64, 64, 16, 128, 128 µg ml⁻¹, respectively. Zhu et al. [202] synthesized ZnO NPs from Cinnamomum camphora (L.) (C. camphora L.) at pH values 7, 8, and 9 with corresponding sizes of 13.9, 15.2, and 21.1 nm, respectively. The antifungal activity was evaluated against A. alternata. The MIC of ZnO NPs was 20 mg l⁻¹ at pH 7, which showed the best antifungal effect. It was found that ZnO NPs induced excessive accumulation of malondialdehyde in A. alternata, causing damage to the cell membrane and thereby leakage of protein and nucleic acid. Despite that ZnO NPs exhibited antimicrobial activity, it was noticed that their sensitivity against fungi was lower compared to bacteria. This is attributed to the ability of fungi to form resistant spores when they grow under aggressive conditions [203].

7.6 Antiviral activity of ZnO NPs

The green synthesis of ZnO NPs demonstrated antiviral activity against many viruses. Melk et al. [204] synthesized ZnO NPs (32.58 ± 7.98 nm) from the alcoholic extract of Plumbago indica (P. indica), a valuable source of alkaloids, phenolics, and saponins. The results showed that ZnO NPs and the plant extract exhibited inhibitory effects against herpes simplex virus type 1 (HSV-1), which could be considered a promising adjuvant to improve the efficacy of HSV-1 drugs. In another study, Melk et al. [205] synthesized ZnO NPs (38.29 ± 6.88 nm) from the alcoholic extract of the flowering aerial parts of Plumbago auriculata Lam (P. auriculata Lam). The ZnO NPs and the plant extract possessed a significant antiviral activity against avian metapneumovirus subtype B, which would be beneficial for controlling the spreading of the virus in infected birds. Moreover, the green synthesis nanocomposites of ZnO NPs/activated carbon (ZnO NPs/AC) (30–70 nm) were prepared using the water hyacinth (Pontederia crassipes) [206]. In addition to the antiviral activity against the HSV1 virus, the ZnO NPs/AC nanocomposites showed antibacterial and antifungal activities. Studies revealed that the mechanism of the antiviral activity of ZnO NPs is attributed to the damage of the lipid membrane and RNA, thus inactivating the virus [207]. Hamdi et al. [208] conducted a computational analysis to investigate the interaction between ZnO NPs and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets. It was found that the hexagonal and spherical ZnO NPs with a crystallite size of ∼11 nm and positive zeta potential exhibited the highest antiviral activity. Recently, Alrabayah et al. [209] used the alcoholic leaf extract of Cestrum diurnum L. (C. diurnum L.) and zinc acetate to prepare green-synthesized ZnO NPs (3.4–4.9 nm) to evaluate their antiviral activity against human corona-229E (HCOV-229E). The C. diurnum L. leaf extract contained catechin, ferulic acid, chlorogenic acid, and syringic acid. Both ZnO NPs and the C. diurnum L. extract showed antiviral activity against HCOV-229E with IC₅₀ of 7.01 and 61.15 µg ml⁻¹; however, their combination showed higher activity than individually with IC₅₀ of 2.41 µg ml⁻¹.

7.7 Antiparasitic activity of ZnO NPs

The antiparasitic activity of the green-synthesized ZnO NPs has been reported in the literature [17]. The antiparasitic mechanism of ZnO NPs involves the disruption of the parasite membrane, damaging the parasite DNA, inhibition of protein synthesis, and formation of free radicals [17]. Dorostkar et al. [210] tested the anthelmintic activity of ZnO NPs and FeO NPs against Toxocara vitulorum (T. vitulorum) using different concentrations of NPs (0.004, 0.008, and 0.012% w/v). The results showed that both NPs increased the mortality rate of worms and increased the levels of malondialdehyde (MDA) and nitric oxide (NO). The levels of MDA and NO increased with an increase in the exposure time and concentration of NPs. The anthelmintic activity of both NPs was attributed to the induction of oxidative/nitrosative stress, resulting in the generation of ROS. Saleh et al. [211] studied the antiprotozoal effects of the metallic NPs (gold, silver, and ZnO) against Ichthyophthirius multifiliis (I. multifiliis), a ciliated protozoan ectoparasite of fish. The results showed that silver and ZnO NPs at 10 and 5 ng m⁻¹ killed 100 and 97% of theronts, respectively, and inhibited the production of tomonts after 2 h of exposure. However, the antiparasitic effect of gold NPs was lower compared to that of silver and ZnO NPs, killing 80 and 78% of tomonts and theronts, respectively, at 20 ng ml⁻¹ after 2 h of exposure. Recently, spherical and elliptical ZnO NPs (34.2 nm), greenly synthesized using the aqueous extract of Himalayan Columbine (Aquilegia pubiflora), were evaluated for their anti-leishmanial activity. The results showed a dose-dependent cytotoxic effect of ZnO NPs against Leishmania tropica (KWH23) with IC₅₀ of 48 and 51 µg ml⁻¹ for promastigote and amastigote, respectively [212]. Likewise, Najoom et al. [213] green-synthesized ZnO NPs (70–90 nm) using the leaf extract of Rhazya stricta (R. stricta) as capping and reducing agents. ZnO NPs showed antiplasmodial activity against plasmodium parasites with IC₅₀ of 3.41 µg ml⁻¹. Similarly, spherical- or elliptical-shaped ZnO NPs (66 nm) were prepared from the aqueous fruit extracts of Myristica fragrans (M. fragrans) and evaluated for their antiparasitic activity [195]. The results showed potential leishmanicidal activity against two forms of parasites (promastigote and amastigote) with a mortality rate of 71.5 and 61.4%, respectively. Hence, these studies demonstrated that the green-synthesized ZnO NPs could be effective against parasites.

7.8 Anti-inflammatory activity of ZnO NPs

The green-synthesized ZnO NPs showed excellent activity toward inflammation [15]. The anti-inflammatory mechanism involves the dissolution of ZnO NPs, releasing Zn²⁺ ions. The release of Zn²⁺ can be involved in several pathways, such as suppressing the release of the pro-inflammatory cytokines (interleukin-1 (IL)-1), IL-1β, IL-13, and tumor necrosis factor-α (TNF-α)) in mast cells. Additionally, Zn²⁺ release can suppress the expression of the lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2) gene in macrophages, inducible nitric oxide synthase (iNOS), myeloperoxidase, and NF-κβ. Moreover, Zn²⁺ release may block the caspase-1 enzyme in activated mast cells [15].

Nagajyothi et al. [191] green-synthesized ZnO NPs using the root extract of P. tenuifolia. The anti-inflammatory activity of ZnO NPs was evaluated in LPS-stimulated RAW 264.7 murine macrophages. The results showed a dose-dependent suppression effect of ZnO NPs on mRNA and protein expression of iNOS and pro-inflammatory cytokines. Rajakumar et al. [186] green-synthesized ZnO NPs (57–115 nm) from the leaf extract of Andrographis paniculata (A. paniculata). By using heat to induce albumin denaturation, the results showed an inhibition in the protein denaturation after exposure to ZnO NPs. Recently, the green-synthesized ZnO NPs, prepared from the leaf extract of Kalanchoe pinnata (K. pinnata), showed anti-inflammatory activity by inhibiting the production and release of the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and COX-2 [214]. Additionally, Mohammad et al. [215] evaluated the anti-inflammatory activity of spherical ZnO NPs, prepared from the Hyssops officinalis L. (H. officinalis L.) extract, using the mouse paw edema test. The results showed a decrease in edema when treated with a dose of 5 mg/kg ZnO NPs. Similarly, Liu et al. [216] proved the anti-inflammatory activity of ZnO NPs, greenly synthesized from the leaf extract of Vernonia amygdalina (V. amygdalina), against inflammation-induced mice model by reducing the inflammatory response and pro-inflammatory cytokines level in mice. Recently, Abdelbaky et al. [26] proved the anti-inflammatory activity of ZnO NPs (34.1 nm), synthesized by employing the aqueous leaf extract of P. odoratissimum L. as a reducing agent. The anti-inflammatory effect of ZnO NPs was evaluated via an in vitro model of human red blood cells (RBCs) which involves hypotonicity-induced hemolysis. ZnO NPs were able to maximally stabilize the membrane by 95.6% at a dose of 1,000 µg ml⁻¹, compared with the standard indomethacin. Finally, a very recent study by Lopez-Miranda et al. [217] evaluated the anti-inflammatory activity of ZnO NPs, prepared from the sargassum extract. The results revealed that ZnO NPs could inhibit protein denaturation and exhibited higher anti-inflammatory activity than the reference drug diclofenac. Thus, these studies suggested that the green-synthesized ZnO NPs showed promising anti-inflammatory activity.

7.9 Wound healing of ZnO NPs

ZnO NPs showed wound-healing activity [46,218]. Mahdavi et al. [219] investigated the cutaneous wound-healing activity of ZnO NPs (32 nm) prepared using the Ziziphora clinopodioides (Z. clinopodioides) leaf extract. The wound healing of ZnO NPs was confirmed by increasing the level of fibrocytes/fibroblasts, hydroxyl proline, hexosamine, hexuronic acid, and fibrocytes, and decreasing the wound area, total cells, and lymphocytes compared to control groups in rats. Additionally, green and chemical ZnO NPs, loaded into gels, were investigated for wound healing [220]. ZnO NPs were prepared by green synthesis using the Lawsonia inermis (L. inermis) leaf extract. The green and chemical ZnO NP-loaded gels showed promising wound-healing properties with reduced healing time in treated groups when compared with the control group and the green ZnO NPs gels were more effective than the chemical ones. Moreover, Shao et al. [221] reported that the green-synthesized ZnO NPs using the Barleria gibsoni (B. gibsoni) leaf extract and loaded into Carbopol gels showed wound-healing properties due to burns in rats.

Furthermore, the literature reported the effective wound-healing activity of ZnO NPs prepared using aqueous leaf extracts of Coleus amboinicus (C. amboinicus) [222], A. barbadensis [223], and Azadirachta indica (A. indica) neem leaves [224] as reducing, capping, and stabilizing agents. In addition, the literature reported an improved treatment of infected wounds caused by resistant bacteria by the embedding of green ZnO NPs prepared using the Alternanthera sessilis (A. sessilis) leaf extract into cotton fabrics [225], incorporation of ZnO NPs prepared using Ilex paraguariensis (I. paraguariensis) leaves into polymeric electrospun fibers of polyacrylic acid and polyallylamine hydrochloride [226], and gel formulations loaded with green synthesis silver NPs and ZnO NPs, prepared from the Annona squamosa (A. squamosa) leaf extract [227]. Altogether, these studies highlighted more promising biomedical applications of the green-synthesized ZnO NPs. Plants, part of the plants, chemical precursors, and size and biological activity of the green-synthesized ZnO NPs reported in Sections 7.1–7.9 are summarized in Table 2.

Table 2

Plants, part of plants, chemical precursors, size, and biological activity of green-synthesized ZnO NPs

Plant	Part of the plant	Chemical precursor	Size (nm)	Biological activity	Ref.
Aloe vera	Leaf extract	Zinc acetate	40–180	Antibacterial	[148]
Dysphania ambrosioides (D. ambrosioides)	Leaf extract	Zinc nitrate hexahydrate	7–130	Antibacterial	[118]
Punica granatum (P. granatum)	Peel extract	Zinc acetate	10–45	Antibacterial	[104]
Orange fruit	Peel extract	Zinc acetate	20	Antibacterial	[153]
Parthenium hysterophorus (P. hysterophorus)	Leaf extract	Zinc nitrate	10	Antibacterial	[228]
Daphne oleoides (D. oleoides)	Leaf extract	Zinc nitrate hexahydrate	30–44	Antibacterial	[155]
Aloe vera	Leaf extract	Zinc nitrate	40	Antibacterial	[133]
Sesbania grandiflora (S. grandiflora)	Leaf extract	Zinc acetate	45	Antibacterial	[156]
Avocado, papaya, and mango fruit	Fruit extract	Zinc nitrate hexahydrate	11–21	Antibacterial	[157]
Tecoma castanifolia (T. castanifolia)	Leaf extract	Zinc sulfate	70–75	Anticancer	[163]
Banana fruit	Fruit extract	Zinc acetate	NR*	Antibacterial and anticancer	[164]
Cratoxylum formosum (C. formosum)	Leaf extract	Zinc acetate	200–500	Anticancer	[165]
Phoenix dactylifera (P. dactylifera)	Root hair extract	Zinc acetate	31–48	Anticancer	[72]
Cardiospermum halicacabum (C. halicacabum)	Leaf extract	Zinc acetate	10–20	Anticancer	[166]
Deverra tortuosa (D. tortuosa)	Aerial extract	Zinc nitrate hexahydrate	9–31	Anticancer (lung and colon cancer)	[167]
Acorus calamus (A. calamus)	Rhizomes extract	Zinc acetate	50–100	Anticancer and antibacterial	[168]
Vinca rosea (V. rosea)	Leaf extract	Zinc nitrate hexahydrate	16–41	Anticancer, antidiabetic, and antimicrobial	[169]
Onion peel	Waste extract	Zinc acetate	NR*	Anticancer and antimicrobial	[170]
Alpinia calcarata (A. calcarata)	Rhizomes extract	NR*	19	Anticancer	[171]
Aloe barbadensis (A. barbadensis)	Leaf extract	Zinc nitrate	20–40	Anticancer and wound healing	[172]
Borassus flabellifer (B. flabellifer)	Palm fruit extract	Zinc nitrate	55	Anticancer	[173]
Ilex paraguariensis (I. paraguariensis)	Leaf extract	Zinc acetate and zinc nitrate	18–389	Anticancer	[229]
Andrographis paniculata (A. paniculata)	Leaf extract	Zinc nitrate hexahydrate	57–115	Antidiabetic, antioxidant, and anti-inflammatory	[186]
Albizzia lebbeck (A. lebbeck)	Bark extract	Zinc acetate	NR*	Antidiabetic and antioxidant	[187]
Artocarpus gomezianus (A. gomezianus)	Fruit extract	Zinc nitrate hexahydrate	NR*	Antioxidant	[189]
Cassia fistula (C. fistula)	Leaf extract	Zinc nitrate hexahydrate	5–15	Antioxidant and antibacterial	[190]
Polygala tenuifolia (P. tenuifolia)	Root extract	Zinc nitrate hexahydrate	NR*	Antioxidant and anti-inflammatory	[191]
Eucalyptus globulus (E. globulus)	Leaf extract	Zinc nitrate hexahydrate	12	Antioxidant	[192]
Ruta graveolens (L.) (R. graveolens L.)	Stem extract	Zinc nitrate	20–30	Antioxidant and antibacterial	[85]
Ceropegia candelabrum (C. candelabrum)	Leaf extract	Zinc nitrate hexahydrate	12–35	Antioxidant and antibacterial	[193]
Trianthema portulacastrum (T. portulacastrum)	Fruit extract	Zinc sulfate	2–8	Antioxidant	[194]
Sambucus ebulus (S. ebulus)	Leaf extract	Zinc acetate	17	Antioxidant and antibacterial	[109]
Myristica fragrans (M. fragrans)	Fruit extract	Zinc acetate	66	Antioxidant, antibacterial, and antidiabetic	[195]
Pelargonium odoratissimum (L.) (P. odoratissimum L.)	Leaf extract	Zinc acetate	76	Antioxidant antibacterial antiparasitic anti-inflammatory	[26]
Prosopis farcta (P. farcta)	Aerial extract	Zinc sulfate	40–80	Antifungal	[197]
Pomegranate	Peel extract	Zinc nitrate hexahydrate	22.8	Antifungal	[198]
Nyctanthes arbortristis (N. arbortristis)	Flower extract	Zinc acetate	12–32	Antifungal	[201]
Cinnamomum camphora (L.) (C. camphora L.)	Leaf extract	Zinc acetate	14–21	Antifungal	[202]
Plumbago indica (P. indica)	Aerial extract	Zinc acetate	33	Antiviral	[204]
Plumbago auriculata Lam (P. auriculata Lam)	Aerial extract	Zinc acetate	38	Antiviral	[205]
Water hyacinth (Pontederia crassipes)	Raw water hyacinth	Zinc chloride	30–70	Antiviral antimicrobial	[206]
Cestrum diurnum L. (C. diurnum L.)	Leaf extract	Zinc acetate	3–5	Antiviral	[209]
Aquilegia pubiflora (A. pubiflora)	Leaf extract	Zinc acetate	34	Antiparasitic	[212]
Rhazya stricta (R. stricta)	Leaf extract	Zinc chloride	70–90	Antiparasitic	[213]
Kalanchoe pinnata (K. pinnata)	Leaf extract	Zinc acetate	24	Anti-inflammatory	[214]
Hyssops officinalis L. (H. officinalis L.)	Leaf and flower extract	Zinc acetate	20–40	Anticancer anti-angiogenesis, and anti-inflammatory	[215]
Vernonia amygdalina (V. amygdalina)	Leaf extract	Zinc acetate	20–40	Anti-inflammatory	[216]
Sargassum	Plant extract	Zinc acetate	20–200	Anti-inflammatory	[217]
Ziziphora clinopodioides (Z. clinopodioides)	Leaf extract	Zinc nitrate hexahydrate	32	Wound healing	[219]
Lawsonia inermis (L. inermis)	Leaf extract	Zinc nitrate hexahydrate	NR*	Wound healing	[220]
Barleria gibsoni (B. gibsoni)	Leaf extract	Zinc nitrate hexahydrate	30–80	Wound healing	[221]
Coleus amboinicus (C. amboinicus)	Leaf extract	Zinc nitrate	15–20	Wound healing	[222]
Azadirachta indica (A. indica)	Leaf extract	Zinc acetate	52	Wound healing	[224]
Alternanthera sessilis (A. sessilis)	Leaf extract	Zinc acetate	NR*	Wound healing	[225]
Ilex paraguariensis (I. paraguariensis)	Leaf extract	Zinc acetate and zinc nitrate	18–389	Wound healing and anticancer	[226]
Annona squamosal (A. squamosa)	Leaf extract	NR*	NR*	Wound healing	[227]
Calotropis gigantea (C. gigantean)	Leaf extract	Zinc nitrate	16–27	Anticancer	[183]
Salvadora oleoides (S. oleoides).	Leaf extract	Zinc nitrate	12–27	Anticancer and antifungal	[99]
Azadirachta indica (L.) (A. Indica)	Leaf extract	Zinc nitrate hexahydrate	NR*	Antibacterial	[230]
Aloe barbadensis miller (Aloe vera)	Leaf extract	Zinc nitrate	25–40	NR*	[67]
Hibiscus subdariffa (H. subdariffa)	Leaf extract	Zinc acetate	16–60	Antibacterial and antidiabetic	[231]
Ocimum basilicum L. var. purpurascens Benth.-Lamiaceae	Leaf extract	Zinc nitrate	50	NR*	[232]
– Beta vulgaris (B. vulgaris)	Whole plant extract	Zinc nitrate	20	Antibacterial antifungal	[87]
– Cinnamomum tamala (C. tamala)
– Cinnamomum verum (C. verum)
– Brassica oleracea var. Italica (B. oleracea)
Atalantia monophylla (A. monophylla)	Leaf extract	Zinc acetate dihydrate	33	Antibacterial	[233]
Thymbra spicata L. (T. spicata L.)	Leaf extract	Zinc acetate dihydrate	6.5–7.5	Antibacterial, antioxidant protection against DNA damage	[234]
Stevia	Leaf extract	Zinc acetate	10–90	Antibacterial	[235]
Cassia auriculata (C. auriculata)	Leaf extract	Zinc acetate	20–30	Antibacterial	[236]
Phoenix dactylifera (P. dactylifera)	Date pulp waste extract	Zinc hexahydrate	30	Antibacterial	[88]
Chamomile flower (Matricaria chamomilla L, M. chamomilla L), olive leaves (Olea europaea, O. europaea), and red tomato fruit (Lycopersicon esculentum M, L. esculentum M)	Flower, leaf, and fruit extract	ZnO	48	Antibacterial	[237]
Beta vulgaris (B. vulgaris)	Fruit extract	Zinc nitrate	20	Anticancer	[238]
Punica granatum (P. granatum) (pomegranate)	Leaf and flower extract	Zinc nitrate hexahydrate	NR*	Antibacterial	[239]
Justicia adhatoda (J. adhatoda)	Leaf extract	Zinc acetate, zinc sulfate, and zinc nitrate	15–20	Antibacterial	[240]
Mussaenda frondosa L. (M. frondosa L.)	Leaf, stem, and callus extracts	Zinc nitrate hexahydrate	5–20	Antibacterial, anti-inflammatory, anticancer, antidiabetic and antioxidant	[241]
Parthenium hysterophorus (P. hysterophorus)	Leaf extract	NR*	NR*	Antibacterial	[130]
Raphanus sativus var. Longipinnatus (R. Sativus)	Leaf extract	Zinc acetate dihydrate	209	Anticancer	[100]
Citrus sinensis (C. sinensis)	Peel extract	Zinc nitrate hexahydrate	NA	Antibacterial	[242]
Eucalyptus globules (E. globules)	Leaf extract	Zinc nitrate hexahydrate	52–70	Antifungal	[243]
Salvia officinalis (S. officinalis)	Leaf extract	NR*	NR*	Antifungal	[128]
Ziziphus nummularia (Z. nummularia)	Leaf extract	Zinc nitrate	17	Antifungal and anticancer	[196]
Syzygium cumini (S. cumini)	Leaf extract	Zinc acetate	30	Antioxidant and anticancer	[92]
Cissus quadrangularis (C. quadrangularis)	Stem extract	Zinc acetate dihydrate	75–90	Antibacterial and anticancer	[244]
Sabal blackburniana (S. blackburniana)	Leaf, fruit, and pollen grains extracts	Zinc acetate dihydrate	2–50	Acetylcholinesterase inhibitory activity and anti-Alzheimer	[245]
Amygdalus scoparia (A. scoparia)	Stem bark extract	Zinc acetate dihydrate	15–40	Anticancer, antidiabetic, and antibacterial	[246]
Cnidoscolus aconitifolius (C. aconitifolius)	Leaf extract	Zinc acetate	100	Antioxidant, anti-inflammatory, and antibacterial	[247]
Solanum rantonnetii (S. rantonnetii)	Leaf extract	NR*	12	Antifungal activity	[248]

NR*: not reported.

8 Toxicity of ZnO NPs

Although bulk ZnO has been GRAS [35], there is still doubt regarding the safety of ZnO NPs on human health that warrants further investigation [249]. Because ZnO NPs are commonly used in broad biomedical applications, the advantages of these types of NPs must be wisely weighed against possible toxic effects [250]. It has been shown that the concentration and exposure time of NPs and cell type play a vital role in posing toxic effects [251]. Additionally, the toxicity of NPs is determined by their physicochemical properties such as size, shape, composition, and surface properties [252].

Moatamed et al. [253] compared the impact of ZnO NPs (39 nm) and bulk ZnO (5 µm) on the liver function of Wistar rats. Three groups of rats received three dose levels of ZnO NPs according to body weight (bw) (25, 50, and 100 mg/kg bw). It was found that the group that received 100 mg/kg bw ZnO NPs showed the most significant changes in liver enzymes, histopathological structure, and oxidative stress markers, indicating a dose-dependent hepatic toxicity of ZnO NPs. However, the group that received 100 mg/kg bw of bulk ZnO showed no significant effects on liver function. This can be explained by the increase in the Zn²⁺ concentration in the hepatic tissues of rats treated with ZnO NPs, while no significant change in Zn²⁺ concentration was found in rats that received the same dose of bulk ZnO. A study by Salami et al. [254] determined the hemolytic toxic effects of ZnO NPs and their bulk counterparts on isolated RBCs. A concentration range of 0.01–1 mM of ZnO (bulk and NPs) was used in this study. The results demonstrated that ZnO NPs caused toxic hemolytic effects due to the generation of ROS, lipid peroxidation, and GSH depletion, whereas bulk ZnO did not show any toxic hemolytic effects. Additionally, Roy et al. [255] assessed the impact of ZnO NPs versus bulk ZnO on the activity of murine macrophages. The study revealed that ZnO NPs were more potent in activating the proinflammatory cytokine production by macrophages, whereas the small size of ZnO NPs may help in the evasion of the macrophage response.

The toxicity studies of green-synthesized ZnO NPs are limited. Saranya et al. [256] assessed the in vitro cytotoxicity of three green-synthesized NPs including ZnO NPs, FeO NPs, and copper NPs (Cu NPs), prepared using the aqueous leaf extract of Musa ornate (M. Ornate) and Zea mays (Z. mays). The cytotoxicity of NPs was assessed in three cell lines, the African green monkey kidney cell line (Vero), pig kidney cell line (PK15), and Madin Darby bovine kidney (MDBK) at 24 and 48 h. The results showed that the cytotoxic effect of green NPs varied based on the concentration and exposure time of NPs and cell type. Additionally, the green ZnO NPs exhibited higher cell viability at lower concentrations (10 µg/100 µL) when compared to green FeO NPs and Cu NPs in all cell types [256]. Additionally, the toxicity of the ZnO NPs, prepared from the aqueous extract of Amaranthus caudatus (A. caudatus), was evaluated using zebrafish embryos [257]. The toxicity of ZnO NPs showed a concentration-dependent pattern, where the ZnO NP concentration of ≤10 mg ml⁻¹ showed no toxic effect, whereas at 50–100 mg ml⁻¹ high levels of mortalities were observed [257].

The toxicity of chemically synthesized ZnO NPs was evaluated. Earlier, Najim et al. [258] investigated the cytotoxicity of ZnO NPs of different sizes in both normal and cancer cell lines. The results showed that ZnO NPs of 85.7 and 190 nm displayed cytotoxic effects on all cell lines derived from the lung tissue (Hs888Lu), neuron-phenotypic cells (SH-SY5Y), neuroblastoma (SH-SY5Y), human histiocytic lymphoma (U937), with no effect on lung cancer (A549). Additionally, it was found that the toxicity of ZnO NPs depends on the particle size, concentration, and exposure time. Khan et al. [259] assessed the toxic effect of ZnO NPs at different concentrations (50, 100, 250, and 500 ppm) on human erythrocytes. ZnO NPs showed a concentration-dependent hemolytic activity in red blood cells. Additionally, the genotoxic potential of ZnO NPs, investigated by the in vitro alkaline comet assay, showed concentration-dependent DNA damage at 250 and 500 ppm concentrations. The toxic effects of ZnO NPs were attributed to the generation of ROS that resulted from oxidative stress. Moreover, the in vitro cytotoxicity of ZnO NPs (25 nm) on an in vitro model cell line, obtained from the gill tissue of Wallago attu (WAG), was evaluated by MTT, neutral red uptake, and LDH assay tests [260]. Researchers found that ZnO NPs induced acute toxicity to WAG cells with IC₅₀ of 5.7 ± 0.1, 3.1 ± 0.1, and 5.6 ± 0.12 mg l⁻¹, respectively. Uzar et al. [261] studied the nephrotoxic potential of ZnO NPs (10–50 nm) against rat kidney epithelial cells (NRK-52E) at 25–100 µg ml⁻¹ exposure concentration. The IC₅₀ on NRK-52E was 73 µg ml⁻¹. Comet assay, used to assess the genotoxic effect of ZnO NPs at 12.5–50 µg ml⁻¹, showed significant DNA damage in NRK-52E cells. Additionally, Saranya et al. [256] assessed the in vitro cytotoxicity of three green-synthesized NPs including ZnO NPs, FeO NPs, and Cu NPs, prepared using the aqueous leaf extract of Musa ornate (M. Ornate) and Zea mays (Z. mays). The cytotoxicity of NPs was assessed in three cell lines, the African green monkey kidney cell line (Vero), pig kidney cell line (PK15), and MDBK at 24 and 48 h. The results showed that the cytotoxic effect of green NPs varied based on the concentration and exposure time of NPs and cell type. Additionally, the green ZnO NPs exhibited higher cell viability at lower concentrations (10 µg/100 µL) when compared to green FeO NPs and Cu NPs in all cell types. Furthermore, Yousef et al. [262] confirmed the hepatic and renal toxicity of ZnO NPs in male Wistar rats, when ZnO NPs were daily administered orally for 75 days. Despite these studies, there is no standard methodology for assessing the toxicity of ZnO NPs [263]. Therefore, more toxicological studies are still needed to provide information on the safety, risk assessments, and risk management of ZnO NPs.

9 Challenges associated with the translation process of ZnO NPs from bench to market

The translation process of ZnO NPs from bench to market is facing several potential bottlenecks and challenges. The green synthesis of ZnO NPs may suffer from batch-to-batch reproducibility and large-scale production including plant selection, synthesis conditions, NPs’ size, and applications [24,264]. For instance, plants used for the green synthesis of NPs are commonly selected based on their local availability and abundancy [264]. This, in turn, makes it difficult to green-synthesize NPs globally, using specific plant extracts. Additionally, the time of plant collection hinders their use, where plants are either collected during flowering or fruiting seasons [265]. Moreover, the green synthesis of NPs requires extremely high or low temperatures, long reaction and extraction times, inert conditions (i.e., prepared under an inert atmosphere of argon or nitrogen), and the use of chemical precursors (such as zinc nitrate and zinc acetate) [264]. In addition, the specific reaction mechanism of the green synthesis of NPs is still difficult to elucidate, and the mass balance and stoichiometric ratio that scale up the process is a major challenge. Furthermore, the size of NPs, synthesized from different plant extracts, is heterogeneous with irregular shapes [264].

The safety profile of ZnO NPs needs to be thoroughly investigated and assessed before their use. It was found that ZnO NPs may cause hepatic, nephron, neuronal, pulmonary, and reproductive toxicity [70]. ZnO NPs can enter the biological systems through three primary routes: dermal, inhalation, and ingestion, followed by circulating in the bloodstream [266]. The way zinc interacts with proteins, nucleic acids, and cells plays a crucial role in determining the application of ZnO NPs. Additionally, factors such as size, physicochemical properties, dose, and duration of exposure are important considerations in assessing the toxicity of ZnO NPs [251,252].

The regulatory approval process for novel NPs can be complex and time-consuming. This is because meeting the regulatory requirements for safety, efficacy, and quality can be a challenging and costly process, often leading to a delay in market entry. Moreover, moving from laboratory-scale production to large-scale manufacturing can be a significant hurdle, where ensuring efficient and cost-effective production methods while maintaining product integrity can be a challenge. For example, NPs can be susceptible to changes in the physicochemical properties over time, such as aggregation, agglomeration, or degradation. Hence, ensuring long-term stability and adequate shelf-life for NP-based products is crucial for commercial viability [267]. Therefore, addressing these challenges requires a multidisciplinary approach involving scientists, regulators, and manufacturers. Additionally, thorough research, robust safety assessments, adherence to regulatory guidelines, and efficient manufacturing processes are essential for the successful translation and commercialization of ZnO NPs.

10 Conclusion and future perspectives

Scientists are actively dedicating their efforts to enhance the green synthesis of ZnO NPs for various biomedical applications. The green-synthesized ZnO NPs have gained significant importance due to their eco-friendly, biocompatibility, and cost-effectiveness than those prepared by chemical and physical methods. The variety of plant extracts with their phytochemicals such as flavonoids, terpenoids, polyphenols, tannins, and alkaloids can be considered a potential source for the green synthesis of ZnO NPs that contribute to the stability and discovery of new physicochemical properties for ZnO NPs. Research studies have shown that the green-synthesized ZnO NPs exhibited superior bioactivities due to the presence of various phytochemicals on their surfaces. The antibacterial activity of ZnO NPs holds promise as a potential solution for the treatment of infections caused by multidrug-resistant bacteria and as an alternative to antibiotics. Moreover, as an anticancer agent, ZnO NPs localize in cancer cells through enhanced permeability and retention effects and electrostatic interactions, leading to cell death through the release of Zn²⁺ ions and/or generation of ROS. This suggests that ZnO NPs are a promising anticancer agent in targeting drug delivery. The green-synthesized ZnO NPs may offer a remedy for diabetes as an antidiabetic agent and an increase in the radical scavenging activity as an antioxidant agent. Therefore, ZnO NPs hold vast potential for pharmaceutical and biomedical applications, making them a major area of research. Furthermore, ZnO NPs exhibited antifungal, antiviral, antiparasitic, and anti-inflammatory activities, expanding their use in health care products such as sunscreen lotions for skin acne, blemishes, and UV/visible light protection. However, it is crucial to address the limitations of ZnO NP toxicity toward biological systems and the need for evidence-based research exploring the bioactivities of ZnO NPs, which require further investigation. Currently, to our knowledge, the green-synthesized ZnO NPs have not been introduced into the market, and no clinical trials have been reported. Hence, additional in vivo studies on the biomedical applications of green-synthesized ZnO NPs are necessary for future clinical use.

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Acknowledgments

The authors are thankful to their respective departments/universities for the successful completion of this review.

Funding information: The authors state no funding involved.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Conflict of interest: The authors state no conflict of interest.

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Received: 2023-03-16

Revised: 2023-06-10

Accepted: 2023-08-03

Published Online: 2023-09-01

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/ntrev-2023-0112

Schlagwörter für diesen Artikel

antibacterial activity; anticancer activity; antioxidant activity; antidiabetic activity; toxicity; wound healing; antifungal activity

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Plant mediated-green synthesis of zinc oxide nanoparticles: An insight into biomedical applications

Artikel

Abstract

1 Introduction

2 An overview of zinc and ZnO

3 Chemical and physical methods for the synthesis of ZnO NPs

4 Green synthesis of ZnO NPs

5 Mechanism of green synthesis of ZnO NPs

6 Cytotoxic mechanisms of ZnO NPs

6.1 Release of Zn2+ ions from ZnO NPs

6.2 Production of ROS

6.3 Direct interaction between ZnO NPs and cells

7 Biomedical applications of ZnO NPs

7.1 Antibacterial activity of ZnO NPs

7.2 Anticancer activity of ZnO NPs

7.2.1 Role of ZnO NPs in anticancer activity

7.2.2 Role of ZnO NPs in targeted drug delivery

7.3 Antidiabetic activity of ZnO NPs

7.4 Antioxidant activity of ZnO NPs

7.5 Antifungal activity of ZnO NPs

7.6 Antiviral activity of ZnO NPs

7.7 Antiparasitic activity of ZnO NPs

7.8 Anti-inflammatory activity of ZnO NPs

7.9 Wound healing of ZnO NPs

8 Toxicity of ZnO NPs

9 Challenges associated with the translation process of ZnO NPs from bench to market

10 Conclusion and future perspectives

Acknowledgments

References

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6.1 Release of Zn²⁺ ions from ZnO NPs