Plant-Derived Metal Nanoparticles (PDMNPs): Synthesis, Characterization, and Oxidative Stress-Mediated Therapeutic Actions

: In the 21st century, plant-derived metal nanoparticles (PDMNPs) have gained considerable interest because of their tremendous and remarkable potential as therapeutic agents as well as development of less expensive, safer, and easier biomedical equipment. PDMNPs are synthesized from metal salts or oxides by using plant extracts because plants have diversiﬁed bioactive compounds that can act as reducing and stabilizing agents at the time of nanoparticle synthesis. Besides, PDMNPs take advantages over the nanoparticles synthesized by other methods because of their low cost, environmental friendliness, and sustainability. The present review explains the synthesis of PDMNPs, their characterization techniques, and oxidative stress-mediated pharmacological effects. The mode of actions for antioxidant, antimicrobial, and anticancer properties has also been critically explored. Due to the plethora of data on plant-derived nanoparticles and their pharmacological properties, we have highlighted PDMNPs’ shape, size, metals of use, and experimental ﬁndings regarding their antioxidant, anti-microbial, and anticancer properties in a tabulated form for studies conducted in the last ﬁve years, from 2018 to 2022. Because of our review study, we, herein, contemplate that the scientiﬁc community as a whole will get a greater comprehension of PDMNPs and their numerous therapeutic applications in a single window.


Introduction
The burgeoning branch of science based on nanoparticles (NPs), known as nanoscience and nanotechnology, has attracted a lot of study attention over the past few decades. NPs have been developed widely with unique and dazzling properties ranging in size from 1.0 to 100 nm because they provide the way for advancing multidisciplinary research ranging from medicine to engineering, physics, and chemistry [1]. For several years, NPs have been employed in the manufacture of nanodevices, nanotherapeutics, nanoelectronics, and engineered biological structures, with applications in pharmaceuticals, foods, agriculture, energy, environment, cosmetics, electronics, and catalysis [2]. Because of their tiny size, diverse structure, and numerous biological and physicochemical features, NPs have increasingly caught the attention of the research community over the past two decades [3]. In most of the cases, metal salts/oxides-mediated NPs outperform other nanoparticles due to their huge surface area to volume ratio, excellent biocompatibility, adjustable production, and high stability, making them appropriate for a wide range of applications [3]. Depending on the synthesis methods, NPs may be obtained in various forms, including nanotubes, nanorods, nanoparticles, and nano-sheets, which differ in morphology, size, and form along with optical properties, but they excel in a variety of applications in diverse sectors [4]. The top-down strategy and bottom-up approach are two methods used to create

History and Development of Nanoparticles
NPs made of carbon or other materials such as silver (Ag), gold (Au), or iron (Fe) metals have nanoscopic dimensions ranging from 1 to 100 nanometers in size [20]. They cannot be seen with the naked eye or even a standard microscope [21]. Because of their small size, NPs exhibit high surface energy, and huge surface area, and thus, they have unique and distinct physical and chemical properties from their bulk counterparts [22]. NPs can be made artificially as by-products or by modifying/engineering raw materials that have specific functions. The chemical synthesis of metal-based NPs, including Ag, Au, Fe, copper (Cu), zinc (Zn), palladium (Pd), platinum (Pt), and cobalt (Co) comes to mind when we discuss the different types of nanoparticles [23]. Materials like metal salts, metal oxide, silicates, polymers, organics, carbon, and others are also tuned into nano-size

History and Development of Nanoparticles
NPs made of carbon or other materials such as silver (Ag), gold (Au), or iron (Fe) metals have nanoscopic dimensions ranging from 1 to 100 nanometers in size [20]. They cannot be seen with the naked eye or even a standard microscope [21]. Because of their small size, NPs exhibit high surface energy, and huge surface area, and thus, they have unique and distinct physical and chemical properties from their bulk counterparts [22]. NPs can be made artificially as by-products or by modifying/engineering raw materials that have specific functions. The chemical synthesis of metal-based NPs, including Ag, Au, Fe, copper (Cu), zinc (Zn), palladium (Pd), platinum (Pt), and cobalt (Co) comes to mind when we discuss the different types of nanoparticles [23]. Materials like metal salts, metal oxide, silicates, polymers, organics, carbon, and others are also tuned into nano-size on a large scale using physical, mechanical, and chemical approaches [24]. Depending on the material from which they are made, nanomaterials can adopt a variety of morphologies such as spheres, cylinders, sheets, or tubes [25]. Nanomaterials can take many different forms, such as zero-dimensional (colloids, quantum dots, nanoclusters, etc.), one-dimensional (nanowires, nanotubes, nanobelts, and nanorod, etc.), two-dimensional (quantum wells, super lattices, and bio membranes, etc.), and three-dimensional (nanocomposites, filamentary composites, as well as for use in everyday items like electrical appliances, vehicles, aircraft, biomedical devices, and medications [40]. Because they are uniform in size, shape, composition, surface charge, and optical properties, metal-based NPs have many advantageous medical and industrial applications. However, the high cost and purity of metals during synthesis is a major concern in the biomedical and pharmaceutical sectors [41,42]. Greener approaches to synthesizing biogenic NPs are constantly in demand by researchers to reduce toxic effects and maintain a green environment because of their biocompatible, clean, cost-effective, and eco-friendly properties [43,44]. equipment [38]. Chemical methods include the reduction, precipitation, hydrothermal, sol-gel, emulsion, and micro-emulsion processes. The most widely used technology among them is sol-gel because of its flexible implementation and high yield. Chemical processes are faster at producing bulk materials, but they also require expensive, hazardous substances that are detrimental to the environment and our health [39]. The synthesis of NPs using salts or oxides of metals such as Ag, Au, Pt, and Pd has attracted a lot of attention in recent decades due to the need to create materials that are safe for the environment, society, and economy, as well as for use in everyday items like electrical appliances, vehicles, aircraft, biomedical devices, and medications [40]. Because they are uniform in size, shape, composition, surface charge, and optical properties, metal-based NPs have many advantageous medical and industrial applications. However, the high cost and purity of metals during synthesis is a major concern in the biomedical and pharmaceutical sectors [41,42]. Greener approaches to synthesizing biogenic NPs are constantly in demand by researchers to reduce toxic effects and maintain a green environment because of their biocompatible, clean, cost-effective, and eco-friendly properties [43,44].

Plant Mediated Synthesis
Use of fungi, bacteria, plant, and plant-derived products are the best examples and best studied topics currently to synthesize green NPs over conventionally synthesized NPs [45]. However, the production of NPs by microorganisms like bacteria and fungi is a costly and time-consuming process, and since microbes are the main contributor to many diseases, high-grade care is always needed. PDMNPs do not pose these dangers and typically preserve positive health effects. In the suspension of plant extracts and metal salts/oxides, the synthesis of PDMNPs is completed in three steps, viz., activation, growth, and termination [46]. The synthesis begins with the activation of metal salts/oxides by reducing them followed by the growth of smaller nanoparticles into larger NPs, and finally, with the production of desired nanoparticles [47]. The usage of plant extract helps to overcome the poor solubility, decreased stability, and extended duration, which are the main drawbacks of the synthesis of metal NPs ( Figure 3). The aqueous extracts of the leaves of numerous plants have received the most attention among plant extracts for the production of metal-chelated NPs [48]. Given the rapid rate of synthesis, short reaction times, and repeatable yields of Ag and Au, these metals are excellent choices for creating plant-based NPs [49]. All plant parts, including the flowers, leaves, stems, fruits, and roots, are abundant sources of bioactive compounds, which include terpenoids, polyphenols, flavonoids, and tannins. Numerous studies have demonstrated that various plant

Plant Mediated Synthesis
Use of fungi, bacteria, plant, and plant-derived products are the best examples and best studied topics currently to synthesize green NPs over conventionally synthesized NPs [45]. However, the production of NPs by microorganisms like bacteria and fungi is a costly and time-consuming process, and since microbes are the main contributor to many diseases, high-grade care is always needed. PDMNPs do not pose these dangers and typically preserve positive health effects. In the suspension of plant extracts and metal salts/oxides, the synthesis of PDMNPs is completed in three steps, viz., activation, growth, and termination [46]. The synthesis begins with the activation of metal salts/oxides by reducing them followed by the growth of smaller nanoparticles into larger NPs, and finally, with the production of desired nanoparticles [47]. The usage of plant extract helps to overcome the poor solubility, decreased stability, and extended duration, which are the main drawbacks of the synthesis of metal NPs ( Figure 3). The aqueous extracts of the leaves of numerous plants have received the most attention among plant extracts for the production of metal-chelated NPs [48]. Given the rapid rate of synthesis, short reaction times, and repeatable yields of Ag and Au, these metals are excellent choices for creating plant-based NPs [49]. All plant parts, including the flowers, leaves, stems, fruits, and roots, are abundant sources of bioactive compounds, which include terpenoids, polyphenols, flavonoids, and tannins. Numerous studies have demonstrated that various plant extracts contain polyphenols, flavonoids, tannins, quinol, chlorophyll, and saponin, contributing as reducing, capping, and stabilizing agents to improve the stability of PDMNPs [50].
When PDMNPs are synthesized, the bioactive compounds found in plant extracts provide great stability, reduce the clumping, as well as inhibiting the agglomeration, which promotes good dispersion and more active sites in the suspension [51]. These bioactive compounds have a variety of functional groups, including carboxylic acid (-COOH), aldehyde (-CHO), hydroxyl (-OH), nitrile (-CN), and amines (-NH 2 ), which are engaged in reducing metal ions into free metals ( Figure 4) like Ag + → Ag 0 , Au + → Au 0 , Cu 2+ → Cu 0 , Zn 2+ → Zn 0 , and Pt + → Pt 0 [52]. Bioactive compounds also improve the adsorption ability of NPs by increasing the surface area of PDMNPs through molecular interactions such as electrostatic interaction, dipole-dipole induction, π-π interaction, and hydrogen bonding [53]. According to research studies, functional groups of bioactive compounds are involved in reducing the energy gap in metals, which promotes electron release and makes it easier for free radical species to develop. They may readily pass through the cell membrane of pathogens and other host cells followed by killing the diseased cells and as a result, they exhibit a variety of biological activities such as antioxidant and anticancer [54]. In some studies, polyphenols and flavonoids form a capping layer around the NPs via electrostatic interactions, which increases the PDMNPs' ability to bind to bacterial cell surfaces [55]. Copper-based PDMNPs have been synthesized by using Cu(NO 3 ) 2 salt and plant extracts. In these studies, the bioactive compounds such as anthraquinone glycosides, tannin, and quercetin contained in plant extracts have been found to play key roles in enveloping and stabilizing the PDMNPs by reducing Cu 2+ ions into Cu 0 form [56,57]. Furthermore, Kumar et al. reported the formation of highly stable Zn nanoparticles when they used a suspension of Citrus paradisi peel extract and zinc oxide. Following these studies, researchers found that the hydroxyl and carboxyl functional groups of flavonoids, carotenoids, and limonoids were involved in reducing the Zn 2+ ions into Zn 0 , a zero valent state [58]. Moreover, Kesharwani et al. demonstrated that alkaloids, amino acids, and sugar compounds reduce Ag + to Ag 0 [59]. Therefore, these investigations supported the significance of bioactive compounds in the synthesis of PDMNPs by demonstrating how they operate as reducing, capping, and stabilizing agents. extracts contain polyphenols, flavonoids, tannins, quinol, chlorophyll, and saponin, contributing as reducing, capping, and stabilizing agents to improve the stability of PDMNPs [50]. When PDMNPs are synthesized, the bioactive compounds found in plant extracts provide great stability, reduce the clumping, as well as inhibiting the agglomeration, which promotes good dispersion and more active sites in the suspension [51]. These bioactive compounds have a variety of functional groups, including carboxylic acid (-COOH), aldehyde (-CHO), hydroxyl (-OH), nitrile (-CN), and amines (-NH2), which are engaged in reducing metal ions into free metals ( Figure 4) like Ag + → Ag 0 , Au + → Au 0 , Cu 2+ → Cu 0 , Zn 2+ → Zn 0 , and Pt + → Pt 0 [52]. Bioactive compounds also improve the adsorption ability of NPs by increasing the surface area of PDMNPs through molecular interactions such as electrostatic interaction, dipole-dipole induction, π-π interaction, and hydrogen bonding [53]. According to research studies, functional groups of bioactive compounds are involved in reducing the energy gap in metals, which promotes electron release and makes it easier for free radical species to develop. They may readily pass through the cell membrane of pathogens and other host cells followed by killing the diseased cells and as a result, they exhibit a variety of biological activities such as antioxidant and anticancer [54]. In some studies, polyphenols and flavonoids form a capping layer around the NPs via electrostatic interactions, which increases the PDMNPs' ability to bind to bacterial cell surfaces [55]. Copper-based PDMNPs have been synthesized by using Cu(NO3)2 salt and plant extracts. In these studies, the bioactive compounds such as anthraquinone glycosides, tannin, and quercetin contained in plant extracts have been found to play key roles in enveloping and stabilizing the PDMNPs by reducing Cu 2+ ions into Cu 0 form [56,57]. Furthermore, Kumar et. al. reported the formation of highly stable Zn nanoparticles when they used a suspension of Citrus paradisi peel extract and zinc oxide. Following these studies, researchers found that the hydroxyl and carboxyl functional groups of flavonoids, carotenoids, and limonoids were involved in reducing the Zn 2+ ions into Zn 0 , a zero valent state [58]. Moreover, Kesharwani et al. demonstrated that alkaloids, amino acids, and sugar compounds reduce Ag + to Ag 0 [59]. Therefore, these investigations supported the significance of bioactive compounds in the synthesis of PDMNPs by demonstrating how they operate as reducing, capping, and stabilizing agents.

Factors Affecting the Synthesis of PDMNPs
There are some challenges during the synthesis of PDMNPs, particularly, non-uniformity in the particle's shape and size, that need to be overcome in order to maintain monodispersity in the suspension phase. There are also some other factors that cause de-

Factors Affecting the Synthesis of PDMNPs
There are some challenges during the synthesis of PDMNPs, particularly, non-uniformity in the particle's shape and size, that need to be overcome in order to maintain monodispersity in the suspension phase. There are also some other factors that cause delays in the production rate, reaction time, and overall yield of synthesized nanoparticles. These factors include the concentration of plant extract, metal salt concentration, incubation time, pH, temperature, types of bioactive compounds, and agitation processes to make the plant extract and suspension of nanoparticles [60].

Effect of Extract Concentration
The concentration of extracts is one of the most important factors that influence the synthesis of PDMNPs as well as the time required for their formation [61]. In most of the studies, generally, the extract volume ranges from 1 mL to 250 mL have been applied to observe their effects on the synthesis [62]. The effects of extract concentration can be easily observed by changes in color while synthesizing PDMNPs. Moreover, color changes have been observed as the ratio of concentrations of plant extract varies, indicating variations in the size of nanoparticles. When the concentration of plant extract containing significant number of bioactive compounds is high, a sharp peak (small particle size) is observed. A broad peak is observed as the concentration of extract decreases, indicating that the size of the nanoparticle is large [63]. Furthermore, Adeyemia et al. synthesized the bimetallic Ag and Au nanoparticles by using different concentrations (50, 100, and 250 mL) of Dovyalis caffra (Kei apple) fruit extract. This study demonstrated that different concentrations of extracts affect the shape and size of nanoparticles with a low reaction time in 250 mL volume [64]. Other researchers also reported the different extract concentrations regarding the best synthesis of PDMNPs using Ocimum sanctum (Tulsi) leaves extract (0.1, 0.2, 0.3, 0.4, and 0.5 mL), Aegle marmelose leaves extract (10, 20, and 30 mL), and Aloe barbadensis Mill. (Aloe Vera) leaves extract (5, 10, and 15 mL) concentrations [65][66][67].

Effect of Time
The incubation period of suspension containing plant extract and metal salts/oxides is a vital period that influences the synthesis of PDMNPs in an appropriate time. Smaller-size nanoparticles are produced by using a short incubation time, but larger nanoparticles with a propensity to assemble are often produced by employing a longer incubation time [68]. Numerous investigations have shown that the ideal incubation time, during which all essential reaction steps are properly carried out, is in between 30 min and 2 h. By using Garcinia indica fruit extract, Sangaonkar et al. successfully carried out the experiment of UV spectroscopy to investigate the incubation time from 2.0 to 120 h in a reaction mixture and then found that 24 h was the ideal incubation time for the synthesis of Ag nanoparticles. Similar to this, when fruit extract from Garcinia indica was utilized as a reducing agent, the Au ions are reduced, followed by transformation into nanoparticles in less than two hours [69,70]. In the earlier studies, by using the extracts of Chenopodium leaf and Tansy fruits, Ag and Au nanoparticles started to appear within 10 min of the reaction started and increased up to 2 h by the time the reaction was finished [71,72]. In contrast, other research indicated that the incubation period was slightly longer than the recommended 2 h [73,74]. Additionally, several reports indicated that the ideal incubation duration for the nucleation reactions used to generate metal nanoparticles from plant extracts is 60 min, indicating great stability of the metal nanoparticles [75,76].

Effect of pH
The parameter of pH cannot be ignored at the time of nanoparticle synthesis because it affects the morphology of nanoparticles in terms of shape and size [77]. The absorbance peaks in UV-Visible absorption spectra throughout their investigation make it simple to see changes caused by pH variations [78]. The formation of big-sized nanoparticles at pH 2.0 and large amounts of smaller-sized nanoparticles at pH 3.0 to 4.0 during the synthesis of gold nanoparticles using Avena sativa plant extract demonstrate the strong pH dependence of nanoparticle size [79]. Another study found that increasing the pH from 3.0 to 7.0 causes nanoparticle size to decrease, whereas increasing the pH from 7 to 11 causes nanoparticle size to rise [80]. Similarly, by using some other plant extracts, studies hypothesized that higher pH (alkaline) values produce small, mostly spherical nanoparticles whereas lower pH (acidic) values produce big, ellipsoidal nanoparticles [81][82][83][84]. According to an experiment performed by Chitra and Annadurai, the size of Ag nanoparticles synthesized using Bacillus brevis cell culture was highly dependent on pH changes, with larger size (60-110 nm) at pH 5 and smaller size (10-40 nm) at pH 9 [85]. Moreover, Suresh et al. reported the synthesis of smaller size nanoparticles derived from low-pH ginger extract, which was attributed to the presence of the highest total phenolic content as compared to neutral and alkaline pH extracts [86]. Overall, pH influences the size and shape of PDMNPs because exposure of polar functional groups such as carbonyl and hydroxyl groups increase the stability as well as binding ability of metal ions during the nucleation and growth phases, which encourages less aggregation of synthesized nanoparticles [87].

Effect of Temperature
Another crucial factor that must be monitored throughout the synthesis of nanoparticles is temperature. A rise in temperature typically speeds up the reaction, increasing the amount of product produced. For instance, the rate of nanoparticles formation is higher at high temperatures than it is at normal temperature [88]. The greater yield of synthesized nanoparticles is made possible by an increase in metal reduction and homogenous nucleation, both of which are influenced by temperature. It is interesting to note that the temperature range needed for the synthesis of PDMNPs is lower (37-100 • C) than the temperature range needed for synthesis using physical and chemical methods, which is around 350 • C [89]. Because of the increment in surface plasmon resonance and sharpness of peak by increasing temperature, Ag and Au nanoparticles have been synthesized at higher rates at higher temperatures, transitioning from nanorod to platelet-shaped size, as reported in various research [90][91][92][93]. Additionally, some research used spectrophotometers to analyze the strong peaks of absorbance, which directly linked the experiment's increased temperature to the nanoparticle's rapid growth [94]. The sharpness of the absorbance relies on the size of the synthesized nanoparticles.

Effect of Types of Bioactive Compounds
Plant extracts rich in bioactive compounds (polyphenols, flavonoids, tannins, saponin, etc.), which function as reducing and stabilizing agents, influence the reduction of metal ions, the size, shape, processing, and stability of the PDMNPs [95]. These variations are explained by the presence of varying amounts of phytochemicals, which rely on extract preparation techniques, species variances within the same plant, and geographical and seasonal variations [96]. There are many publications on PDMNPs that reported the use of bioactive compounds as reducing, capping, and stabilizing agents, but no clear study is available so far on which types of phytochemicals are responsible for these properties. Most often, the reported bioactive compounds are polyphenols, flavonoids, terpenoids, and alkaloids, which contain oxygen functionalities and could act as reductants of metal ions for the synthesis of PDMNPs [97,98]. Some publications showed that ascorbic acid and glucose could reduce some metals like Au and Ag into their zero valent states, leading to PDMNPs synthesis [99]. Proteins, enzymes, and sugars found in plant extracts also lead to bio reduction of metals as well as agglomeration of synthesized nanoparticles [100,101]. Thus, the various types of bioactive compounds, which are good reducing and capping agents, may enhance the yield of synthesized PDMNPs by inhibiting the aggregation of the nanoparticles.

Effect of Agitation
Naturally, bioactive compounds are synthesized in cytoplasm or in specific cells and organelles, followed by transportation to other organs. Among them, terpenoids and alkaloids are synthesized in chloroplast whereas the endoplasmic reticulum contains the steroids and sesquiterpenoids. Plant vacuoles contain water-soluble compounds like polyphenols, flavonoids, saponins, and tannins. Lipid soluble compounds such as monoterpenoids and fats are transported through resin ducts and lactiferous glands from their origin sites to storage locations [102]. Most of the compounds are synthesized in the leaves and aerial parts and stored in other parts like roots, fruits, and stems. Thus, a metabolic profile based on bioactive compounds that varies from species to species of plants depends upon season, time, and stage of development [103]. It also depends on the location and types of compounds by which extraction should be done so that we can obtain bioactive compounds in good yield [104]. Agitation during extraction is a very important aspect that should be done because most of the bioactive compounds are enclosed within the cells or vacuoles. Usually, proper agitation causes the breakdown of the cell walls or vacuole rupturing, followed by enhancing the squeezing out of the compounds [105]. Hot aqueous extraction, among them, is the best way for easy preparation of PDMNPs. In this type of extraction, polar compounds are widely extracted, the majority of which are polyphenols and flavonoids, along with their glycosides. Further, when compounds are extracted for an extended time of period, their yield improves [106][107][108]. In addition, pressurized agitation of plant material is very important; applying pressure increases extraction yield [109].

Structural Characterization of PDMNPs
To ensure the reproducibility in terms of therapeutic potential, production, and safety after the completion of synthesis, thorough characterization of synthesized nanoparticles is crucial [110]. Basic physicochemical techniques such as UV-Visible absorption spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), Raman spectroscopy, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and powder X-ray Diffraction (XRD) are used to characterize the NPs based on their shape, dispersity, size, and surface area. There are also some more recent methods that are available and frequently used in modern times, including X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), energy dispersive X-ray spectroscopy (EDX), field emission scanning electron microscopy (FE-SEM), etc. (Table 1) [111].

Ultra Violet-Visible Spectroscopy
UV-Visible absorption spectroscopy is an easy-to-use technique that clearly displays the peak's absorbance. Strong or weak bands on the peak indicate how stable a synthesized nanoparticle is, and these optical features include reaction time, temperature, pH, and concentration of suspension [112]. For Ag and Au metals, the majority of the synthesized nanoparticles are visible at wavelength ranges of 400-450 nm and 500-550 nm, respectively [113].

X-ray Crystallography
X-ray crystallography is a powerful method to characterize the crystal structure and phase identification of synthesized nanoparticles in which X-rays strike the crystal surface and then interact with the atoms to measure the crystallinity [114]. On the crystalline plane, the atoms organize themselves properly and display a diffraction pattern [115]. According to multiple research papers, several PDMNPs have resulted in crystalline structures with average particle sizes of about 25-30 nm [116][117][118][119][120].

Fourier-Transform Infrared Spectroscopy (FTIR)
Fourier-transform infrared spectroscopy (FTIR) is used to depict the chemical information, particularly functional groups (amide, hydroxyl, and carboxyl groups), along with bonds parameters [121]. By locating the bioactive compounds present in plant extracts, Future Pharmacol. 2023, 3 261 which may serve as coating/capping and stabilizing agents during the reduction processes of metal into their respective ions, FTIR is used to extract useful information about the surface chemistry of synthesized PDMNPs [122]. In addition to identifying functional groups, FTIR also identifies stretching and vibrational frequencies, such as C=O, C=C, C-H, and C-O, demonstrating that a functional group can change from a raw plant extract to a synthesized nanoparticle [123]. The chemical behavior of PDMNPs has been well documented in the literatures [124][125][126][127][128].

Microscopic Techniques
High-resolution microscopies such as SEM, TEM, and AFM depict the morphological characterization of nanoparticles. Data are collected in two-dimensional images using the SEM technique via a selection of areas under study. The generated image depicts spatial variations in morphological properties (size distribution, shape, aggregation, and dispersion), as well as information on the sample's qualitative chemical composition [129]. There is also a high-resolution SEM technique called FE-SEM that offers deeper pictures of molecules in their native condition. The direct imaging method TEM, on the other hand, shows particle size, size distribution, and morphology. It has a resolution that is around one million times better than the wavelength in simple light microscopy [130]. Numerous scientists and researchers have used SEM and TEM to characterize numerous examples of PDMNPs in terms of particle size, distribution, aggregation, and chemical contents [131][132][133]. The AFM technique, which analyses 3D pictures of samples with information on size, shape, sorption, dispersion, and aggregation as well as surface properties of particles, is an improvement over the SEM and TEM approaches [134].

Powder XRD Technique
By examining the crystalline structure (orientation, phases, and lattice parameters) of samples in powder form, this approach may characterize the NPs and compare them to established structural databases. Because atoms in a crystal are arranged at the proper distance, when X-rays hit the crystal surface and interact with the atoms, they produce a diffraction pattern [135]. The XRD experiment yields two peaks, where a broad peak denotes amorphous powder and a sharp peak denotes the crystalline form of synthesized NPs [136]. The XRD method has been used in numerous studies to characterize the PDMNPs in order to ascertain the crystalline properties of samples, and in the majority of cases, samples displayed a strong diffraction pattern that was closely correlated with the emergence of NPs [137][138][139][140]. In contrast, EDX is a unique and adaptable tool for obtaining a sample's composition map or performing an area-specific elemental analysis. This method involves stimulating samples with electrons or high-energy photons and then detecting the spectrum of the released photons [141].

Light Scattering Methods and Zeta-Potential (ζ)
Two significant non-destructive/invasive methods that are based on the light scattering concept are dynamic light scattering (DLS) and zeta-potential to determine the physicochemical properties of NPs. When they are distributed in colloidal suspension under various conditions, including concentration, pH, temperature, and time, DLS assesses the diameter and stability of the NPs. DLS also relies on the particle's diffusive motion. Particles that are more massive will move more slowly than those that are smaller. Zeta potential, on the other hand, is used to describe the surface charge of NPs and learn more about their physical stability and interactions with other molecules on their surfaces [142]. DLS has been widely used in recent years to measure the size of PDMNPs that have been reduced to nano-size ranges between 1.0 and 200 nm [143,144]. The values of Zeta potential are crucial indicators of a nanoparticle's stability. NPs have a tendency to aggregate at 0-5 mV values, whereas 5-20 mV values indicate that they are poorly stable. The maximum stability of NPs is shown by Zeta potential values above 40 mV [145].

Antioxidant Action
Living cells undergo metabolic reactions and generate free radical species, which cause human diseases (cardiovascular, neurodegeneration, inflammation, and cancer, among others) and ageing by damaging proteins, nucleic acids, lipids, and carbohydrates [147]. Chemicals like propyl gallate (PG), tertiary butyl hydroquinone (TBHQ), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) are widely used as antioxidants that inhibit degenerative reactions in processed foods, drinks, juice, and the edible items but, when used for a long time, they have negative impacts on the human body [148]. Despite the availability of chemical antioxidants, there is growing interested in the development of nano-antioxidants due to their low cost as well as lack of deleterious side effects. Many researchers have synthesized a large number of metal NPs from plant extract for their antioxidant properties because medicinal plants as well as metals such as Ag, Au, Cu, Zn, Fe, and Pd have been well known for their antioxidant properties in traditional medicines since antiquity [149]. Many bioactive compounds, including polyphenols, flavonoids, terpenoids, tannins, and saponins, are abundant in plants and act as reducing, capping, and stabilizing agents for the synthesis of PDMNPs by reducing the metal ions into their zero-valent state. Because of fine-tuning in surface area, particle size, and surface activity, PDMNPs have attracted a lot of attention recently for their powerful antioxidant effects. These agents exhibit good biocompatibility and action stability [150]. As shown in Figure 5, metals can readily donate an electron to quench free radicals, according to their chemical structure, and act as powerful antioxidants on their own in nature. For their antioxidant activity, metals salts of Ag, Au, Pd, Pt, Zn, Cu, and metal oxides like copper oxide (CuO), zinc oxide (ZnO), nickel oxide (NiO), and magnesium oxide (MgO) are frequently utilized [151]. Numerous medicinal plants and nanoparticles synthesized by their extracts along with free radical scavenging properties are well studied [152][153][154][155][156] [157,158]. Nanoparticles derived ROS that facilitate the damaging of the cell membrane of microorganisms, as well as cancerous cells, are resulted into antimicrobial and anticancer effects. The scavenging capacity of ROS derived from PDMNPs, can be easily determined by using ROS or other free radical quenching-based assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), trolox equivalent antioxidant capacity (TEAC), oxygen radical absorbance capacity (ORAC), total oxy radical scavenging capacity (TOSC), total radical-trapping antioxidant parameter (TRAP), cupric-reducing antioxidant capacity (CUPRAC), and chemiluminescence methods [159]. Although DPPH, FRAP, TEAC, TOSC, ORAC, TRAP, and CUPRAC methods are simple, standardized, and the most recognized antioxidant assays, the chemiluminescence methods have advantage over them because they are a highly sensitive analytical method that gives quenching capacity of ROS at very low concentration [160]. Due to the low detection limit, luminol, lucigenin, pholasin, and peroxyoxalate are used as chemiluminescence reagents to generate the excited state by producing light which is diminished by the oxidant initiator such as HO • , O 2 • , ROO • , ONOO − , or HOCl [161]. The total antioxidant capacity of various plant extracts and their NPs by the chemiluminescence method was also reported in many studies [162]. Most of the methods are based on luminol-H 2 O 2 chemiluminescence, lucigenin-H 2 O 2 chemiluminescence nano-enzyme based sensor, and NaHCO 3 -H 2 O 2 -Co 2+ chemiluminescence reactions to measure the antioxidant activities of various fruit, herbs, and medicinal plants extracts along with dietary substances such as soft drinks and wines [163][164][165][166][167]. The chemiluminescence assay is also reported to evaluate the antioxidant activity in pomegranate and honey samples [168]. Additionally, herein, we present an in-depth mechanism of ROS-mediated antimicrobial and anticancer properties of PDMNPs. Table 2 shows the antimicrobial and anticancer activities of PDMNPs over the last five years (2018-2022).

Antimicrobial Action
Infections caused by various pathogenic microorganisms have become a major lenge for the entire world, and the problem is worsening due to the uncontrolled indiscriminate use of antibiotics to prevent the infections. Since multidrug resis (MDR) poses a severe threat to the spread of epidemic infections, the researchers' e sive efforts to find new medicines have been insufficient [169]. The development o

Antimicrobial Action
Infections caused by various pathogenic microorganisms have become a major challenge for the entire world, and the problem is worsening due to the uncontrolled and indiscriminate use of antibiotics to prevent the infections. Since multidrug resistance (MDR) poses a severe threat to the spread of epidemic infections, the researchers' extensive efforts to find new medicines have been insufficient [169]. The development of sustainable, alternative techniques to reduce antibiotic exposure and their resistance has recently attracted a lot of attention and it is unsurprisingly growing quickly [170]. PDMNPS have been noteworthy as emerging antibacterial agents in the current context because of their high surface area to volume ratio and distinctive chemical diversity. PDMNPs are observed in a variety of shapes when reactions are completed, including spherical, hexagonal, triangular, truncated, octahedral, rod-shaped, and flower-shaped. PDMNPs with different shapes have a large surface-volume area, which facilitates their antimicrobial actions by interacting with biological components of microorganisms via various mechanisms such as membrane disintegration, cellular component damage (DNA, protein, lipids, and electron transport chain), and the generation of ROS ( Figure 5) [171]. Thus, PDMNPs may be promising options for combating MDR microorganisms and overcoming microbial resistance. PDMNPs have shown inhibitory activities against both Gram-positive and Gram-negative bacteria, fungi, and various viruses as a safe, eco-friendly, and simple platform for developing anti-microbial agents [172].
However, many reports have proposed antimicrobial mechanisms mediated by NPs, but the precise mechanism is unknown. PDMNPs have antimicrobial activity because they release metal ions. Metal ions interact with the cell membrane to form pits or gaps, which cause cell membrane damage by deactivating enzyme functions [173]. They also interact with the sulfur or phosphorus functionalities of proteins or DNA, causing metabolic processes to breakdown. Similarly, PDMNPs can cause ROS formation due to lipid/phospholipid membrane oxidation, which leads to the collapse of DNA/RNA/protein architecture within the bacterium cell [174]. The mechanism underlying the nanoparticle's antibacterial action was recently revealed by a study. In this study, PDMNPs were exposed to solar energy, which causes electrons to move from the band gap to the conduction band and produce both free electrons and holes. OH − combines with a hole to make OH • , while free electrons react with O 2 to create O 2 • . ROS that was produced as a result of this antibacterial activity disrupted cell membranes, allowed cytoplasm to leak out, damaged mitochondria and DNA, and ultimately caused cell death [175]. According to a literature review, due to the high toxicity of Ag ions or Ag-based products against microbes, Ag is the most commonly employed metal for the synthesis of PDMNPs as antibacterial agents [176]. Ag and Ag-products in the form of nanoparticles have been or are being employed as preservatives in the development of nanomedicine, cosmetics, and the food sector due to their small size and huge surface area [177].
Additionally, due to the existence of a thick peptidoglycan layer that serves as a barrier to the penetration of nanoparticles, Gram-positive and Gram-negative bacteria demonstrated different antibacterial efficacy [178]. Most studies concluded that Ag nanoparticles are more effective antibacterial agents against Gram-positive bacteria than Gram-negative bacteria. Some studies, however, have speculated that Ag is more effective for Gramnegative bacteria [179]. According to a different study carried out by Singh and colleagues, Gram-positive bacteria are covered in a thick layer of peptidoglycans and straight-chain polysaccharides that are cross-linked with embedded proteins, giving the cell stiffness and making it difficult for PDMNPs to bind to the cell surface. In contrast, Gram-negative bacteria have negatively charged lipopolysaccharides that are bonded to positively charged silver metal [180]. Tiwari et al. discovered the mechanism by which Zn-based PDMNPs generate ROS. These ROS increase lipid peroxidation, DNA damage, protein, and nucleic acid leakage, as well as reducing the microorganism cell viability. Furthermore, the Zn 2+ ions released by PDMNPs contribute to the damage of microorganism cell membranes during molecular interactions [181]. When Zn nanoparticles bind with biomolecules through electrostatic interactions, Zn 2+ ions are released at the target site, where they cause the oxidation of proteins and lipids, which damages cells [182]. Similar to this, it has been revealed that nanoparticles made of Ti metal generate ROS, when exposed to ultraviolet light. According to this study, ROS prevent oxidative phosphorylation from occurring in the cell membrane, which results in cell death [183]. PDMNPs use a similar antibacterial mechanism to destroy fungal species by releasing metal ions that produce ROS and other free radicals [184]. The enzymatic action of glucan synthase or N-acetyl glucosamine on components such as mannoproteins, 1,3-D-glucan, 1,6-D-glucan proteins, chitin, as well as polysaccharides like chitin, glucan, and mannan or galactomannan, is what creates the cell walls of fungi. These enzymes interact with the metal ions and ROS produced by PDMNPs to display antifungal action [185]. Figure 5 also depicts the antifungal activity of PDMNPs when they interact with the cell membrane or cell wall, allowing intracellular components to leak out. Free radicals, in particular, react with sulfur and phosphorus functionalities in the cell wall to disrupt redox homeostasis. Furthermore, free radicals disrupt fungal growth by interfering with DNA replication, protein synthesis, and enzymatic activity [186]. PDMNPs also interact with glutathione-producing enzymes (antioxidants), reducing fungi resistance [187]. Despite these findings, a more detailed mechanism for the action of PDM-NPs against pathogenic bacteria (both Gram-positive and Gram-negative) and fungi is still required. Table 2 shows the antimicrobial activities of PDMNPs over the last five years (2018-2022).

Anticancer Action
According to the WHO database, cancer is currently the world's top cause of death, accounting for close to 10 million deaths globally in 2020. By 2025, it is anticipated that this number would rise to 19.3 million, with the majority of the patients being from emerging nations [188]. Therefore, it is vital that focus be given globally to accurate cancer detection and subsequent therapy. There are numerous medicines available to treat the various forms of cancer, but these treatments have side effects, particularly when they harm healthy cells, tissues, and organs, which lower down the quality and length of life [189]. Anticancer agents have essentially demonstrated three proposed mechanisms for combating various types of cancer. The first is the apoptotic pathway's target, which is dependent on an increased level of ROS, which causes oxidative stress and DNA fragmentation in the cancerous cell. The second is the interaction of cancer cell proteins/DNA, and the last is anticancer agents interacting with cell membranes to alter cell permeability and mitochondrial dysfunction [190]. The diagnosis of cancer is also a crucial step before treatment, which involves the common use of methods including tissue biopsy, microscopy, and histopathology assay. These techniques, however, only reach a minimal amount of tissue, which causes cells to proliferate quickly and develop into the metastatic stage. While receiving surgical or chemotherapeutic treatment, this cascade makes it difficult to target the cancer cells. However, positron emission tomography (PET), computed tomography (CT) scan, and magnetic resonance imaging (MRI) approaches can detect the cancers more effectively when using NPs-based imaging agents because they can more precisely reach the target areas [191].
Due to the presence of bioactive compounds, the abilities of medicinal plants to treat cancer have been well documented since antiquity [192][193][194]. The detection, diagnosis, and therapy of cancer have also been investigated using a wide variety of metal NPs. As compared to microbial synthesis of nanoparticles, PDMNPs have recently attracted much greater attention since they are clean, safe, and environmentally friendly while bridging the current gap between physical and chemical techniques of their synthesis [195]. According to studies, PDMNPs have a high level of selectivity between cancer cells and healthy cells, which helps to reduce negative effects and provides protection against healthy cell damages. The broad synthesis of PDMNPs by using various metal oxides/salts and plant extracts as green sources has enormous therapeutic potential for the treatment of cancer. Interestingly, Ovais et al. created Ag and Au nanoparticles based on plant extracts to observe tumor progression and evaluate it at the cellular level [196,197]. Although the mode of action of PDMNPs is complex and under investigation, some reports claim that their anticancer activity is due to enhanced apoptosis in cancer, cells via cell cycle arrest as well as activation of ROS and caspase-3 mediated signaling. Finally, in cancerous cells, they cause mitochondrial depolarization and DNA damage [198]. NPs develop intracellular membrane-bounded vesicles when they are exposed to the cancer cell surface, which permits them to enter the cells and produce reactive oxygen species. These species exhibit a series of abnormal behavior, including mitochondrial dysfunction, enzyme inactivation, protein oxidation, damage to nuclear materials (DNA/RNA), etc., and as a result, develop the cancer disease [199]. The cell cycle is stopped in the growth phase at the time of mitosis and meiosis, based on a 2017 study by Patil and Kim. By increasing the ratio of B-cell lymphoma protein 2-associated X and B-cell lymphoma protein, ROS causes cells to be more susceptible to apoptosis [200]. This one is followed by stimulation of caspase-3, -8, and -9 to help accelerate apoptosis. Two years later, Kim et al. demonstrated in their experiment that ROS increases the quantity of P53, a tumor protein that fights against cancer cells. Researchers noted in the same study that smaller NPs could kill more cancer cells because they can enter the cell membrane more readily and acquire a larger surface area. Therefore, it seems reasonable that ROS production aids PDMNPs in their fight against cancer [201]. Table 2 lists the anticancer investigations of PDMNPs for the last five years (2018-2022).

Future Outlooks and Directions
PDMNPs have a wide range of applications in the regulation of oxidative stressmediated disorders and diseases, according to recent research advances. Evidence from the published literature suggests that PDMNPs could be used as novel and effective therapeutics to treat diseases caused by oxidative stress. Due to the availability of diverse bioactive compounds, medicinal plants and herbs have been utilized as traditional medicine for thousands of years. This gives patients more treatment alternatives than are available with synthetic medications. Particularly, PDMNPs facilitate the large-scale manufacturing of therapeutic compounds and are environmentally safe, inexpensive, and toxin-free, making this method advantageous for the long-term advancement of nanoscience. PDMNPs also have a wide range of medicinal uses, including as an antioxidant, and with antibacterial, antifungal, anticancer, antiplasmodial, and antidiabetic potentials. Additionally, they have the ability to redox the biomolecular reactions in catalytic amounts. More work in the right direction is needed to address the main problems during the synthesis and implementation of PDMNPs as therapeutic agents, based on pharmacological applications. The key issues are as follows: • When produced through physical and chemical processes, nanoparticles are uniform and homogeneous. However, synthesized by biological methods, PDMNPs are variable in shape and size. Consequently, logical investigations need to be employed to ensure the uniformity of particles.

•
The exact amount of reducing agents (bioactive compounds) in plant extracts is unknown if it is not standardized quantitatively. Therefore, plant extract should be standardized qualitatively and quantitatively in order to maintain the homogeneity of formed PDMNPs. • PDMNPs are synthesized using metals, which may be toxic to the human body if consumed in large quantities. Most reports do not include the toxicity profile of synthesized PDMNPs, as well as biological studies. To address these issues of the precise mechanism, distribution, toxicity, and adverse effects, comprehensive pharmacokinetic studies are required extensively.

•
The majority of PDMNP therapeutic applications and molecular mechanisms are based on ROS generated during biological actions. Despite these studies, the negative effects on normal cells/tissues lack a mode of action, which is one of the most pressing issues that must be addressed accurately.

•
Extensive clinical or in vivo research is also required to develop PDMNPs in the appropriate dosage forms for the treatment of a variety of diseases. • Despite ROS-mediated therapeutic actions, other modes of action of PDMNPs must be investigated further in order to be effective against other diseases.

Conclusions
In this review, we summarized the synthesis, characterization techniques, and indepth evaluation of antioxidant, antimicrobial, and anticancer activities of PDMNPs over the last five years. The challenges experienced in the synthesis of PDMNPs and how they should be overcome, as well as their therapeutic activities mediated by oxidative stress, were the main topics of this review. Moreover, we provided the ideal parameters (extract concentration, incubation time, pH, and temperature) to use at the time of PDMNPs synthesis in order to obtain high-yield, low-cost PDMNPs. Additionally, we have discussed the molecular mechanisms of oxidative stress-mediated therapeutic actions along with their findings in tabulated form. Furthermore, we have also highlighted the future outlooks of metal NPs and the changes that must be made in order to develop PDMNPs as safe biocompatible agents. Considering the above scientific benefits and drawbacks of PDMNPs, researchers may fine-tune their research by simplifying their processes to develop such types of PDMNPs as therapeutics against human diseases. Furthermore, in vivo or clinical studies might be needed to evaluate the toxicity and performance of PDMNPs if they are used as therapeutics for long-term use.

Informed Consent Statement:
No animal or in vitro or in vivo study was performed in this manuscript, and therefore, neither ethics nor informed consent was necessary.
Data Availability Statement: Not applicable.
Acknowledgments: Authors are very thankful to the management team of Era University, Lucknow, India, and the American University of Barbados (AUB) for their assistance during this work. We have sincere thanks to Raj Kazmi for providing figure designing assistance.

Conflicts of Interest:
The authors declare no conflict of interest, financial or otherwise.