Green synthesis of gold and silver nanoparticles as antidiabetic and anticancerous agents

ABSTRACT

Green nanotechnology is an eco-friendly method for the biosynthesis of metallic nanoparticles, which are being used due to their unique features and bio-applications in various fields. World Health Organization (WHO) stated that the use of medicinal plants to treat a variety of disorders, such as diabetes mellitus (DM), cancer, HIV infection, hepatitis, tuberculosis (TB), and malaria is very effective. Green synthesis is a cost-effective, environment- friendly, and safe method. There are a wide variety of native medicinal plants around the world, owing to their unique physical, chemical, and biological characteristics, used for gold and silver nanoparticle (NP) synthesis, and are potent among all metal nanoparticles. However, as an alternative to several traditional techniques to synthesize nanoparticles, green chemistry has arisen. This review covers the green synthesis of AuNPs/AgNPs and its significance as a potent anticancer and antidiabetic agent. All literature surveys will be helpful in terms of further progress as to go from summarizing or concluding data along challenges and future perceptions.

GRAPHICAL ABSTRACT

KEYWORDS:

• Green nanotechnology
• phytochemicals
• gold and silver nanoparticles
• diabetes mellitus
• cancer

1. Introduction

The largest interdisciplinary fields (1) that work at the nanoscale (1 to 100 nm) are known as nanoscience (2) and nanotechnology (3). The capacity of living cells, and how to alter materials at the nanoscale scale was first reported by Norio Taniguchi of Tokyo University in 1974 (4). Nanoparticles have a large surface area (5–7), which makes it easier for them to interact with various functional ligands (8). Despite their tiny size (9) they may be employed in a variety of fields (10), such as biomedicals (11), pharmaceutics (12), and for the treatment of environmental hazards. A novel alternative to the traditional procedures (13) for the production of nanoparticles, green nanotechnology is a clean, non-toxic, and environment-friendly method (14). This also employs microorganisms (15,16), plant biomass, or extracts (17). Metallic nanoparticles, such as silver (Ag) (18), gold (Au) (19), platinum (Pt) (20), and palladium (Pd) (21), have been thoroughly researched in recent years compared to bulk metals or metal ions (22). Gold and silver metal nanoparticles (23) have drawn a lot of interest in the fields of catalysis (24), optics (25), sensing (26), imaging (27), and biomedical devices (28).

The synergistic capabilities of the plant and metal NPs (29) are important in phyto-nanotherapy (30) because they provide therapeutic benefits that may be clinically bioequivalent to those of many synthetic medicines (31). Diabetes (32), often known as diabetes mellitus or just diabetes, is a syndrome of excessively high blood sugar levels (32) brought by a malfunctioning metabolism and also due to inherited environmental factors (hyperglycemia) (33). According to data from the Centers for Disease Control (CDC), diabetes is the sixth largest cause of disease-related mortality in the U.S. (34) and the third major cause among some ethnic communities. It is observed that its prevalence is growing at an alarming rate around the globe (35). Diabetes was expected to be the fifth leading cause of death in the Americas in 2019 among persons aged 20 or older, which accounted for 409,000 deaths (36).

One in six fatalities (or 9.6 million people) was caused by cancer in 2018, also helps in making it one of the top causes of death (37). However, 70% of cancer deaths take place in middle- and low-income nations (38). The most popular methods for treating and managing cancer are surgery (39), chemotherapy (40), radiation therapy (41), and hormone therapy (42). Diabetes mellitus patients are more likely to develop malignancies (43) such as pancreatic (44), colon (45), liver (46), kidney (47), bladder (48), and breast (49). According to the estimates of WHO, 12.4 million individuals received a cancer diagnosis in 2008 (50) and additionally, about 6.6% of people worldwide have diabetes. Patients who have both DM and cancer are more common and have several risk factors (51,52). Rapid insulin and insulin-like growth factor 1 (IGF-1) receptors (53) are found in cancer cells (54), and these receptors can help in cell survival (55), proliferation (56), mitogenesis (57), and metastasis (58). The discovery of treatments for cancer and diabetes has progressed over time, but access and the expense of treatment remain key issues.

Nanotechnology-based therapeutics (59) and diagnostic methods (60) have recently shown effective results for increasing cancer treatment (61) and are also one of the most promising research topics that are currently seen as a frontier in medicine (62). Since ancient times, the valuable metal silver has been employed extensively in medicine (63) and the founder of modern medicine (64) Hippocrates thought that silver could heal wounds (65) and alleviate sickness (66).

This review covered green nanotechnology its significance, phytochemicals effective against diabetes and cancer, synthesis of gold/silver nanoparticles along their anti-diabetic and anti-cancerous potential, and their future prospects.

2. Green synthesis of nanoparticles (NPs)

Plants are inexpensive, low-maintenance chemical factories of the nature (67). There have been reports of the synthesis of AgNPs and AuNPs utilizing biological sources such as plants (68), bacteria (69), fungus (70), lichen (71), seaweed (72), and algae (73). This environmentally benign technique might offer an alternative to the chemical and physical synthesis of AgNPs (74). In recent years, many plants have been employed effectively for the production of silver and gold nanoparticles outside the cells (75). The synthetic yield of plant-assisted nanoparticle synthesis is much greater than those of other biosynthetic methods (76). Due to the presence of various phytochemicals in different plant parts such as fruit, leaves, stems, and roots, they have been widely exploited for the green production of nanoparticles (77). Chemical-reducing agents, such as hydrazine, sodium citrate, and sodium borohydride, were used to reduce the respective precursor salts to produce homogenous suspensions in the most typical production of metallic nanoparticles (78).

The procedure for the synthesis of nanoparticles starts with gathering the desired plant's parts from accessible locations, cleaning them thoroughly twice or three times using tap water to get rid of dirt and soil, and then washing them again in sterile distilled water to get rid of any leftover particles (79). These crisp, clean plant parts are dried under shade for 5–7 days before being ground in a home blender and the powder is stirred with distilled water to make the plant broth. A few mL of plant extracts and a 10⁻³ M AgNO₃ solution allow for the reduction of pure Ag⁺ ions to Ag (80) which can be observed by taking periodic readings of the solution's UV-visible spectra (81). Plant extracts and microorganisms also function as reducing agents and capping or stabilizing agents, preventing the nanoparticles from aggregating (82). The general method for the synthesis of nanoparticles by green technology is presented in Figure 1.

Figure 1. Green synthesis of nanoparticles.

3. Significance of green synthesis

Nanoparticle (NP) production mediated by plants is favored over synthesis by microorganisms (83). The latter is impractical since it calls for more aseptic circumstances, a laborious procedure, and a longer incubation period (84). The green production of silver and gold nanoparticles is now a developing and significant area of nanotechnology. It has become more popular since it is less harmful when compared to chemical risks (85) and is economical along environment-friendly. Green synthesis compared to other methods, offers numerous advantages in the production of nanoparticles, such as ecologically safe, high yield, needs less time, easy to synthesize, and uses cheaper and less toxic solvents (86). They also consume less energy and perform at moderate operating temperatures. According to this claim, silver nanoparticles produced by plants are more biologically active than those produced by other chemical processes (87).

Green synthesis is straightforward and typically involves a one-pot reaction (88). It is scaleable, toxic chemicals are removed, increasing the product's biocompatibility with healthy tissues for in vivo applications (89, 90). This procedure is also economical, having several possibilities for other metallic NPs in biological and industrial applications. The uses of green-synthesized metallic NPs have been extensively reviewed (91). Some of the most important significant factors that assist green synthesis are shown in Figure 2.

Figure 2. Significance of green synthesis.

4. Phytochemicals as potent antidiabetes and anticancerous agents

Plants contain high concentrations of secondary metabolites called phytochemicals that are thought to have little or no impact on the growth and nutrient requirements of plants. The chemical structure of the plant-based diabetes drugs i.e. berberine (92), procyanidins (93), calycosin (94), nigellicimine (95), thymohydroquinone (96), isoquinoline (97), camptothecin (98), ferulic acid (99), strychinine (100), asaronic acid, ellagic acid (101), cassiaside (102), caffeic acid (103), and apigenin (104), are given in Figure 3.

Figure 3. Phytochemicals active against diabetes.

Many of these drugs have undergone modifications to produce more effective analogs in terms of activity, toxicity, or solubility. Phytochemicals that have been used against cancer such as vincristine (105), vinblastine (106), taxol (107), podophyllotoxin (108), combretastatin (109), xanthatin (110), geraniol (111), curcumin (112), flavonoids (113), withanolide (114), honokiol (115), indrubin (116), quercetin (117), caffeic acid (118), piperine (113), emodin (119), resveratrol (120), catechins (121), and phenethyl isocyanate (122) have been reported several times by the researchers. Chemicals structures of anticancerous phytochemicals are presented in Figure 4.

Figure 4. Phytochemicals active against cancer.

An extensive variety of secondary metabolites with various chemical structures are produced by plants that are essential for a variety of physiological processes and interactions with the environment. The likelihood of discovering substances is rising with particular anticancer characteristics. Compared to other synthesized anticancer medications, many plant-based secondary metabolites are potentially more biocompatible and less harmful to healthy human cells (123). Plant-based secondary metabolites synergistically act with other chemical elements to enhance the medicinal benefits of the plant as a whole (124). Some secondary metabolites may be more bioavailable than synthesized substances as to absorb more effectively in the body and interact with cancer cells. Secondary metabolites (>800), including norstictic acid, usnic acid, salazinic acid, chloroatranorin, atranorin, and stictic acid, are present only in lichen species that have potential pharmacological effects including anticancer, antibacterial, antiviral, analgesic, anti-inflammatory, and antigenotoxic activities (125).

Although many bioactive secondary metabolites are often found in very low quantities, they make extraction of these compounds difficult and laborious (126). Depending on variables including climatic circumstances, plant age, and geographic location, the composition of secondary metabolites in plants can change dramatically. The regularity and dependability of their anticancer action may be impacted by this fluctuation. In contrast to manufactured medications, plant extracts lack standardized compositions, which might lead to differences in therapeutic effectiveness and dose management (127). Some secondary metabolites with anticancer effects could potentially be harmful to healthy cells and also finding a dosage that is both safe and effective might be difficult. Petroselinum crispum, Apium graveolens, and Matricaria recutita are only a few examples of the plant species that comprise apigenin that belongs to the flavone class and its effective formulations are difficult to obtain due to lower bioavailability and specificity (128). The use of reserpine has decreased significantly, most likely as a result of its unclear mechanism of action and several deceptive side effects brought on by large doses of the drug (129).

5. Green synthesis of AuNPs /AgNPs nanoparticles

A variety of plants are used for the synthesis of gold and silver nanoparticles, as reported by various researchers. A literature survey regarding the green synthesis of NPs will be helpful for the readers to get a deep insight into methodology, reaction conditioning, and optimization in a summarized way. Phytochemicals with reducing properties can facilitate the conversion of metal ions, such as silver ions (Ag⁺) or gold ions (Au⁺), into their corresponding metallic forms (Ag⁰ or Au⁰) (130). These phytochemicals can donate electrons to the metal ions, thereby reducing them and leading to the formation of metallic particles (131). This reduction process is often aided by the presence of appropriate reaction conditions, such as temperature, pH, and the presence of other compounds. Phytochemicals can also help stabilize the particles formed during the synthesis or reduction processes. Different phytochemicals may exhibit varying degrees of effectiveness in metal reduction and stabilization processes (132). Metallic nanoparticles tend to aggregate or oxidize due to their high surface energy and reactivity. Phytochemicals can act as capping agents or surface stabilizers, preventing the particles from agglomerating or undergoing further oxidation (133). By binding to the particle surfaces, these phytochemicals can form a protective layer and enhance the stability and dispersibility of the nanoparticles. Some examples of phytochemicals commonly studied in relation to metal reduction and stabilization include flavonoids, phenolics, terpenoids, and proteins (134).

The green production of silver nanoparticles was accomplished using silver nitrate (AgNO₃), normalized saline, Tween-80, and alcoholic extracts of lichens: Flavopunctelia flaventior, Xanthoria parietina, and deionized water by stirring at 80°C for 2 hrs. The synthesized nanoparticles were characterized by XRD technique (71). Cumin oil, extracted from the seeds of the Nigella sativa L plant, has anti-diabetic potential and was used to synthesize AgNPs using 1 mM AgNO₃ (90 mL) by combining with cumin oil (10 mL), and characterized using UV/Visible spectroscopy (135). The Solanaceae family member; Datura stramonium seed extract (1 mL) along with 1 mM HAuCl₃ (40 mL) employed for AuNPs synthesis and characterized with UV/Vis, FTIR, and SEM that disclosed that AuNPs were agglomerated in the form and were spherical (136). The ethanolic extract of Bauhinia variegate was used for AuNP synthesis by the chemical reduction method using tetrachloroauric acid (HAuCl₄) and trisodium citrate (Na₃C₆H₅O₇.2H₂O). In the second step cetyltrimethylammonium bromide was used to promote stabilization (CTAB), TEM and XRD were used to characterize the AuNPs (137). Moringa oleifera (MO) leaves were used to synthesize gold nanoparticles (AuNPs). The HAuCl₄.3H₂O (90 mL of 1.0 mM) aqueous solution was mixed with MO extract (10 mL) dropwise, and a shift in color from light yellow to ruby red, indicates the bio-reduction of Au³⁺. The SEM, EDS, and UV/Vis spectroscopy were used for characterization (19). AuNPs were synthesized from the Asteraceae family using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and auric chloride (HAuCl₄.3H₂O). Characterization was done with the help of UV/Visible spectroscopy, XRD, FTIR, SEM, TEM, DLS, and AFM (138). Solvents, such as ethanol, ethyl acetate, and hexane, were used for the crude extraction of Leucosida sericea followed by the purification of procyanidins via column chromatography. The purified phytochemical was used for the production of gold nanoparticles (139). From the Fabaceae family, Au/AgNPs were synthesized using aqueous Bauhinia tomentosa leaf extract (5 mL), AgNO₃ (1 mM), and HAuCl_4. H₂O (1 mM), color shifts from pale yellow to ruby red and from pale yellow to reddish brown indicated the synthesize of Au and Ag nanoparticles, respectively (140). The family Moringaceae includes the plant Moringa oleifera was used to synthesize NPs using silver nitrate (AgNO₃) and tetrachloroauric acid (HAuCl₄) 2:3 ratio (141). Gold chloride (HAuCl₄) 4 mM, Marsdenia tenacissima leaf extract was mixed and diluted to 20 mL followed by incubation for 12 hrs resulting in the formation of the targeted compounds. Characterization techniques, such as XRD, SAED, EDAX, UV/Visible spectroscopy, and FTIR, were used to examine nanoparticles (142). Abelmoschus esculentus (L) extract was prepared using triple-distilled water, chloroauric acid (4 mL) was added and stirred continuously for 6 hrs and left for 18 hrs. The color changed from colorless to light purple served as a proof for the synthesis of nanoparticles (143). Taxus baccanta dried needles were used to make ethanolic (80%) extract, treated with chloroauric acid (4 mM) at 24^oC for 24 hrs to synthesize nanoparticles (144). Couroupita guianensis flowers were extracted by adding 50 mL of double-distilled water and mixed with chloroauric acid solutions in various ratios (1:9, 2:8, 3:7, 4:6, and 5:5) for 5 min. Utilizing a variety of cutting-edge techniques such as UV-vis spectroscopy, FTIR, XRD, SEM, and TEM, the nanoparticles were analyzed (145). Dendropanax morbifera leaf (5 g) was boiled in 1000 mL of deionized water to make the leaf extract, and used for the synthesis of gold nanoparticles by mixing gold (III) chloride trihydrate. Centrifuged nanoparticles were then cleaned with deionized water and TEM, EDX, JEM, DLS, and XRD, as well as UV-vis spectroscopy were used for characterization (146). Solanum xanthocarpum leave extract (5 mL) was added to auric chloride (45 mL of 1 mM solution), and the mixture was constantly agitated. In this process, Au ^+ 3 is reduced to Au⁰, resulting in the formation of AuNPs (147). The synthesis of colloidal mono-dispersed AuNPs (20 nm) with Withanolide-A from Withania somnifera plant AuCl₃ (0.05%) with TSC (1%), TA (2.5 mM) and aq. K₂CO₃ (150 mM) was stirred for 5 min at 25^oC. For conjugation, Withanolide-A (10 μg) was dissolved in AuNPs (1 mL) incubated overnight in cold room with gentle shaking and for stability, NaCl (10 µL of 10%) solution was added (148). Plant leaves of Indigofera tinctoria were first washed, chopped, and cooked for 20 min in distilled water. To synthesize the AuNPs, the leaf extract (10 mL) was combined with the HAuCl₄ (90 mL of a 1 mM) solution. A microwave oven with operating power and a frequency of 800 W and 2450 MHz, respectively, was used to heat the reaction mixture. UV-vis spectroscopy was used to keep track of the synthesis of AuNPs (149). 10 gram of Mangifera indica (dry seeds) was extracted with water for 5 hrs and the extract was mixed with an auric chloride tetrahydrate (1 mM) solution in a 6:4 ratio. The appearance of ruby red to purple red color suggested the synthesis of nanoparticles. The techniques, such as TEM, EDAX, SEM, FTIR, and DLS, were used for the confirmation of the synthesized nanoparticles (150). para-aminobenzoic acid-quat188-pullulan (PABA-QP) solution (700 μL of 6%) was mixed with HAuCl₄ (280 μL of 5 mM) and stirred at 80°C for 1 h. After synthesis, the effects of pH (4–10), PABA-QP concentration (1–5%) and type of pullulan derivatives (P, QP and PABA-QP) were also evaluated to check the morphology and particle size of AuNP (151). Gold nanoparticles were synthesized by combining 250 mL of 1 mM HAuCl₄ with 50 ml of Stigmaphyllon ovatum leaf extract while stirring continuously for 1 h at 80°C. For further examination and characterization, the prepared nanoparticles were centrifuged, collected, and dried. Transmission electron microscopy (TEM), energy-dispersive X-ray (EDX), and UV/Vis spectroscopy were used to characterize the nanoparticles (152). Crocin (700 mM) was extracted from the stigma of Iranian saffron, which was mixed with gold ions (0.5 mM) by varying concentrations, temperaturess (25 to 75°C), and reaction times (2 hrs 8 weeks), at constant pH (7.5) for the synthesis of gold nanoparticles. However, the morphologies were confirmed using XRD and TEM (153). Musa acuminata flower extract (ethanol and water) was prepared by a Soxhlet apparatus. The hydrogen tetraaurochlorate (III) trihydrate (1 mM) reacted with extract (10 mL) at room temperature and synthesis of NPs was subsequently centrifuged, air-dried and characterized by XRD, SEM, FTIR, EDAX, and UV/Vis spectroscopy (154). Aegle marmelos, Eugenia jambolana, and soursop extract were made from fruits (100 mg) mixed with hydrogen tatraauric (5 mM) separately. The mixture was agitated and the visual inspection proved that nanoparticle production had occurred (155). A leaf extract of Antigonon leptopus was obtained from 8 g of the plant material at a boiled temperature for 30 min in 100 mL of deionized water. A hydrogen tetrachooro-aurate (60 mL of a 1 mM) solution and 8 mL of leaf extract were combined, and the resultant mixture was centrifuged and vacuum-dried at 30^oC. AuNPs were studied utilizing the JEOL JEM 2100, EDX, XRD, FTIR, and UV-100 spectrophotometer (156). A leaf extract of Stigmaphyllon ovatum (100 mL) was mixed with hydrogen tetrarchloroaurate (III) (500 mL of a 1 mM), the reaction mixture was stirred continuously at 85°C for 1 h to synthesize AuNPs. Transmission electron microscopy (TEM), X-ray diffraction (XRD), and Zetasizer Nano-ZS90 were used to analyze the nanoparticles (157). Genipa americana fruit extract was combined with an auric chloride solution (10 ml of 0.5 mM) and a visual confirmation of gold nanoparticles came from color changes from pinkish red to ruby red. Transmission electron microscopy, UV-vis spectroscopy, electron ionization mass spectrometry, dynamic light scattering, quadrupole time-of-flight QTOF mass spectrometry, X-ray diffraction, and Fourier transform infrared spectroscopy were used to characterize the nanoparticles (30). The extract of Juglans regia was mixed with iron nanoparticles, suspended in an aqueous solution of hydrogen tetrachooroaurate (III) in a 1:1 molar ratio to synthesize AuNPs. Numerous techniques such as HR-TEM, JEM-2100F, XRD, UV/Vis, vibrating sample magnetometer VSM, TGA, and FE-SEM were used to characterize the AuNPs (158). The first step in the synthesis of AuNPs is the synthesis of a saffron extract, attained by boiling 50 mg of saffron in 50 mL of water for 15 min. The extract was mixed with HAuCl₄ (20 mL of 0.5 mM) solution in an orbital shaker at 25^oC. The confirmation of NPs synthesis came from a yellow to purple-color shift. Several analytical methods, such as TEM, SEM, UV/Vis, FTIR, XRD, were used to characterize the NPs (159). Tanacetum vulgare fruit extract was made by boiling fruits (50 g) with water (250 mL) followed by mixing extract (1.8 mL) with an auric acid (50 mL of a 1 mM) solution. AuNP characterization with surface plasmon resonance (SPR) was achieved and cubic lattice of NPs was revealed (160). Cathranthus roseus (CR) and Carica papaya (CP) leaves were washed, dried, pulverized, and extracted using the soxhlet equipment. Leaf extract in diverse concentrations (5–200 μL) treated with chloroauric acid (1 mM). XRD, HR-TEM, FTIR, and UV/Vis spectroscopy were used to analyze NPs (161). Anacardium occidentale dried, powdered leaves (10 g), and double-distilled water (50 mL) were stirred overnight. The resulting extract was combined with a chloroauric acid (0.01M) solution and incubated overnight on a magnetic stirrer. Nanoparticles were characterized by UV-vis spectroscopy, PSA, TEM, XRD, SPR, and FTIR spectroscopy (162). Dracocephalum kotschyi leaves (5 g) were extracted with deionized water (75 mL) and mixed with chloroauric acid (10 ml of a 1 mM) solution. The coloration change in the reaction mixture indicated the formation of the targeted particles (163). A dried plant material of Rosa damascena (0.40 g) was extracted and treated with an aqueous solution of hydrogen tetrachlorocuprate (2 mL of 5 mM) that resulted in the synthesis of the targeted compounds. Various analytical methods, including TEM, SEM, UV/Vis spectroscopy, FTIR, X-ray diffraction XRD, and XPS, were used to characterize the nanoparticles (164). The green synthesis of nanoparticles from different plant extracts is listed in Table 1.

Table 1. Green synthesis of silver and gold nanoparticles.

Plant	Plant Part	Types of Nanoparticles	Method of Synthesis	Characterizations	References
E. officinalis	Leaf Extract	AgNPs & AuNPs	AgNO3 and HAuCl4 added to leaf extract and NPs formed in 19 and 2 mins, respectively, Centrifugation (16,000 rpm) for 10 min.	Quasi-spherical (40.37 ± 1.8– 49.72 ± 1.2 nm)	(165)
N. oleander	stem bark Extract	AuNPs	Aliquots of Au(III) solution (11.6 mM), bark extract from 200–4000 mg/L at room 25 ^oC	Spherical (20–40 nm)	(166)
D. viscosa	Dried Leaf Extract	AuNPs	Leaf Extract, 1 mM aqueous HAuCl4, centrifugation (10,000 rpm) for 20 mins	Spherical (20–50 nm)	(167)
F. cirrhosa	Whole Plant Extract	AuNPs	10 mM auric chloride, 10 ml of crude extract, at 30°C. centrifugation (10,000 rpm) for 20 mins.	Spherical (40–45 nm)	(168)
E. thyrsoideum	Plant Extract	AuNPs	HAuCl4.3H2O (25 mL), Extract (10 mL), pH  = 11 and stirred at 75°C for 30 mins, Ruby red coloration and centrifuged (14,000 rpm) for 20 mins	Spherical (9 nm)	(169)
P. dactylifera	Root hair Extract	AgNPs	Biogenic AgNPs by bottom-up method, AgNO3 (0.1 mM), yellowish brown color	Spherical (21–41 nm)	(170)
E. alba	Plant extract	AuNPs	Auric chloride (1 mm), Plant extract, heated at 90°C for 20 mins	Spherical (26 nm)	(138)
Z. spina-christi	Leave Extract	AuNPs	HAuCl4. 3H2O (0.011 M), stirring along heating for 5 mins and brownish-black NPs.	Spherical (0–10 nm)	(171)
S. rechengri	Aerial parts Extract	AgNPs	AgNO3, extract, reaction in sunlight at pH = 7 and by ultrasound 40 Hz at 40°C and pH: 7	Spherical (44–65 nm)	(172)
A.cepa	Onion Bulb Extract	AgNPs	AgNO3 (0.1 M), onion extract, in dark condition, stirred, centrifuged (3000) rpm for 30 mins and brown NPs were obtained	Spherical (49 to 73 nm)	(173)
E. agallocha	Leaves extract	AgNPs	AgNO3 (1 mM) added to 2 mL of aqueous leaf extract, stirred until color changed observed	Spherical (20 nm)	(174)
P. niruri	Leaves Extract	AgNPs	AgNO3 (1 mM), Extract stirred at room temperature, yellow coloration attained	Spherical 30–60	(175)

6. Antidiabetic potential of Au/AgNPs

The inhibition of alpha-amylase and glucosidase, two crucial enzymes in glucose metabolism, is one of the most essential approaches in the management of diabetes. The primary cause of the rise of glucose levels in blood, is the inhibition of amylase and glucosidase, which stops the breakdown of polysaccharides into monosaccharides. Along with starchy meals, an amylase inhibitor reduces the blood sugar spike that occurs regularly. In various investigations conducted both in vitro and in vivo, AgNPs are referred to be alpha-amylase inhibitors. Silver nanoparticles synthesized with leaf extract of Lonicera japonica were employed for α-amylase and α-glucosidase inhibition by DNSA method and IC₅₀ value of α-amylase and α-glucosidase was found to be 54.56 and 37.86 µg, respectively in a dose-dependent manner. The %age inhibition of α-amylase with AgNPs at the dose of 20, 40, 60, 80 and 100 µg/mL was 40, 60, 70, 80 and 90% respectively. At the same concentration, α-glucosidase shows 40, 60, 80, 90 and 100% inhibition, respectively (176). The activity of polyherbal formulation-mehani-based synthesized Ag and Fe (NPs) were compared using ascorbic acid as a standard. The 50 to 250 µg/mL of Ag, Fe and ascorbic acid was utilized for inhibition of α-amylase. At highest concentration (250 µg/ml), % inhibition of Ag, Fe and ascorbic acid was 60, 70.48 and 73.87% respectively. The results showed that FeNPs show high inhibition to the standard, as compared to AgNPs (177).

Sargassum swartzii was used to synthesize gold NPs and evaluated as an anti-diabetic agent. The diabetes was introduced in rats via injection of alloxan (100 mg/kg bodyweight) and BGL was measured on 7th day of injection to confirm the presence of diabetes. AuNPs were inoculated around 0.5 mg/Kg body weight. It was found that blood glucose was lowered to 98 ± 7.2% in diabetic rats administered with AuNPs (178). Cinnamomum tsoi extract-based AgNPs were used to inhibit the activity of α-amylase and α-glucosidase enzymes. The %age inhibition of Cinnamomum tsoi AgNPs was higher than simple extract (Table 2). The 10 and 75 µg/mL of AgNPs showed inhibition of 45 ± 0.83%, 93 ± 1.09% against α-amylase, respectively, while against α-glucosidase was 57 ± 1.35% and 80 ± 1.54%, respectively (191). AuNPs were synthesized from Padina boergesenii extract and diabetic potential was evaluated. Control group contains DMSO, enzyme (α-glucosidase), extract NPs, while the positive group has acarbose. IC₅₀ of AuNPs was 24 μg/mL while for acarbose, it was 39 μg/mL and AuNPs exhibit high potential than standard acarbose (197). Ocimum basilicum and Ocimum sanctum were used to synthesize AgNPs and their inhibition against α-amylase was 59.79 ± 6.91% and 59.57 ± 3.72%, respectively, although for acarbose it was 48.27 ± 1.79% and their IC₅₀ values were 0.016, 0.070, and 0.022 mg/mL, respectively. However against α-glucosidase, it was 89.31 ± 5.32%, 89.31 ± 5.32% and 73.75 ± 12.86%, respectively along with their IC₅₀ values as 0.009, 1.533, and 0.001 mg/mL, respectively (198). AgNPs were synthesized using seed extract of Alyssum homalocarpum and employed for the inhibition of α-amylase and α-glucosidase enzymes using acarbose as standard drug. IC₅₀ value of acarbose and AgNPs against α-glucosidase was 16.9 and 18.01 µg/mL, respectively. However, AgNPs against α-amylase were moderately active with IC₅₀ value 221.87 μg/mL in 100 mg/mL (199). The dose-dependent inhibitory action of the cumin oil-mediated silver nanoparticles on the α-amylase enzyme was checked. The %age inhibition of the α-amylase with doses of 10–100 μg/mL was 30–90% (135). AuNPs in Moringa oliefera extract were synthesized and their in-vitro antidiabetic activity suppressed the amylase activity in a concentration-dependent manner. It was found that by increasing the concentration, the activity was also increased and the IC₅₀ value was 130 μg/mL (19). Dimers, trimers procyanidins fractions, and Leucosidea sericea total extract (LSTE) were used for the synthesis of AuNPs having respective sizes of 24, 21 and 6 nm. The dimers of procyanidins-Au NPs showed the minimum IC₅₀ value of 1.88 µg/mL and trimers of procyanidins-AuNPs showed the highest α-glucosidase activity with IC₅₀ at 4.5 µg/mL (139).

Table 2. Green synthesis of silver and gold nanoparticles and their antidiabetic activity.

Green Source	Source part (Leaves, stem, flower, roots)	Type of NPs (Au/Ag)	Method/Reaction Conditions	Characterization Technique	Size of NPs	Antidiabetic activity	References
Z. officinale and C. amada	Sprouting region	AgNPs	Centrifugation for ten minutes at 5000 rpm	UV/Vis, EDS, XRD, SEM, and FTIR	Spherical shaped (25–30 nm)	α-amylase and α-glucosidase inhibitory activity of Z. officinale = 55.10%, 57.50%, respectively, while for C. amada AgNPs 65.40% and 68.78%	(179)
P. marsupium	Bark and wood	AgNPs	Aqueous soln. of AgNO3 and color changed yellow to brown	UV/Vis and FTIR.	Average particle size = 148.5 nm	The amylase % inhibition by Pterocarpus marsupium at lower conc. =  41.44% and at high conc. =  71.14% and IC50 value = 700 μg/ml	(180)
L. sericea	Aerial parts	AuNPs	Time (72 hrs), temperature (90–100°C) and stirring for just 60 s	LC-MS, UV/Vis, HR-TEM, XRD, and DLS.	Spherical shape (6.3 ± 2 nm)	In vitro evaluation α-amylase and α-glucosidase IC50 values 14.5 ± 0.8 μg/mL and 3.0 ± 0.3 μg/mL, respectively	(139)
F. cirrhosa	Whole plant	AuNPs	Temperature 60°C for 30 mins, centrifugation (1000 rpm) for 20 mins and color changed pale to deep red	UV /Vis, HR-TEM, XRD, and FTIR	Spherical shape (40–45 nm)	Regenerate islets cells of pancreas Increase insulin secretion and restore hexokinase, Glucose-6-phosphatase and fructose-1, 6-bisphosphatase functions	(168)
C.sativa	Leaf extract	AgNPs	Stirring for 12 hrs at 25°C and black coloration.	TEM, FT-IR, FE-SEM, and UV/Vis	Spherical shape (11.5 nm)	α-glucosidase inhibitory activity and IC50 value = 32.31 μg/mL and Ki value = 39.43 ± 7.31	(181)
M. oleifera	Leaf extract	AuNPs	Centrifugation at 10,000 rpm for 15 mins, color changed from yellow to red. color yellow to red observed	HR-TEM, XRD, UV/Vis, EDS, and SEM	Spherical, oval and hexagonal shape (35–51 nm)	α-amylase inhibitory activity IC50 value = 130 μg/mL	(19)
C. cuspidatus	Leaf extract	AuNPs	Shaking at 25°C, by centrifugation. Color changed from light yellow to deep blue	UV/Vis, XRD, TEM, and TGA	Cubic and square shaped	Au NPs (0.75 mg/Kg body wt.) change body weight from 195.8 ± 10.18 to 203.4 ± 9.65, Blood glucose level 98.00 ± 3.12 mg/dL, Insulin 13 ± 1.25 μU/Ml and glycogen 47.12 ± 1.54 mg/g	(182)
H. integrifolia	Leaf extract	AgNPs	50 mL AgNO3 solution, 100 mL leave extract, dried at room 25^oC and color changed from light green to colloidal black	UV/Vis, XRD, FIR, EDX, and FESEM.	Face centered cubic (32–38 nm)	α-amylase inhibitory activity using 25 μL = 60.08 ± 3.38% and using 100 μL = 86.66 ± 5.03%	(183)
A. cepa	Bulbs	AgNPs	50 mL of 0.1M AgNO3, 20 mL extract, centrifuged at 3000 rpm for 30 mins and color changed yellow to brown.	UV/Vis, SEM, and TEM	Spherical shape (49–73 nm)	In vitro evaluation α-amylase and α-glucosidase inhibitory activity was found to be 45% and 23% with 40 μg/mL	(173)
P. guajava	Leaf extract	AgNPs	AgNO3 solution (1 mL), Psidium guajava extract (5 mL), centrifugation at 15,000 rpm for 20 mins and incubation at 38°C	UV/Vis, FTIR, and SEM,	spherical shaped (52.12–65.02 nm)	In vivo evaluation of Psidium guajava NPs (400 mg/kg), Body weight increased from 196.7 ± 3.8 to 209 ± 2.38 and BGL decreased from 243 ± 1.6 to 109.7 ± 0.88 on the 21st day	(184)
P. niveum	Whole plant	AgNPs	Alcholic (100 mg) extract, AgNO3 solution (1 mM), at pH 11 and green coloration appeared	UV/Vis, FTIR, XRD, SEM, EDS	Spherical shape (21 nm)	In vivo evaluation at (10 mg/kg), body weight increased from 142 to 150 and blood glucose level decreased from 265 mg/dL to 140 mg/dL on the 21st day	(185)
T. foenum-graecum	Seed extract	AgNPs and AuNPs	AgNO3, solution (0.001M), extract, chloroauric acid, 0.0009M, color changed brown to green (AgNPs) and light yellow to red (AuNPs)	Zetasizer, SEM, and EDS	Spherical and irregular shapes (73.18 nm)	Blood glucose level decreased from 310.00 ± 23.65 mg/dL to 125.80 ± 2.58 mg/dL	(186)
G. pomace	Fruit waste extract	AgNPs	Grape extract, AgNO3 (1 mM), stirring, centrifuge at 12000rpm, and light brown to dark brown coloration	UV/Vis, EDS, FTIR, Zeta potential, and H-TEM,	Spherical shape (15 to 20 nm)	α-amylase activity with IC50 value is 43.94 µg/mL and for α-glucosidase 48.5 µg/mL	(187)
A. officinalis L. and X, granatum J.	Leaf and bark extract	AgNPs	Extracts, AgNO3 solution (10Mm) centrifuged for 10,000 rpm for 20 min, washed with water, dry at 50 ^OC	UV/Vis, FTIR, XRD, SEM, DLS	Polydispersed and clusters (0–1000 nm)	α-amylase activity of X. granatum and A. officinalis AgNPs are 35.51 to 89.5%, 18.21 to 76.13%, respectively, while IC50 values are 0.13 and 0.15 mg/mL, respectively	(188)
H. foetidum	Leaf and flower extract	AuNPs	Extract (20 mg), chloroaurate (III) solution, color changed Pale yellow to ruby red	UV/Vis, HR-TEM, XRD, FTIR, and DLS	Hexagonal, spherical and triangular (2.02 ± 0.53–12.5 ± 04.3 nm)	Relative glucose uptake IC50 value of α-glucosidase = 40.0 ± 0.2–173.3 ± 0.1 µg/mL IC50 value of α-amylase found to be 35.6 ± 0.1 µg/mL	(189)
C. viscosa	Whole plant	AgNPs	Aqueous extract + 1, 2, 3 mL AgNO3 Heat at 26 ± 2°C color changed from light green to dark brown	UV/Vis, SEM, XRD, FTIR, and TEM	Rod, spherical, and triangular shape and average size (24 nm)	α-amylase and α-glucosidase inhibitory activities using 3 mL. AgNPs are 57.62% and 90.14%, IC50 values are 21.92 ± 1.74 mg/mL and 1.76 ± 1.91 mg/mL, respectively	(190)
E. phyllanthus	Leaf extract	AgNPs	Extract (5 mL) AgNO3 solution, stirrer, centrifuge at 5000 rpm and color changed pale yellow to brownish	UV/Vis, EDX, SEM, AFM, and XRD	Spherical shape (25–55 nm)	Glucose level decreased 280.83 ± 4.17 to 151.17 ± 3.54 mg/dL	(14)
C. tsoi	Leaf extract	AgNPs	Leaf extract, 2 ml of 5 mM AgNO3 heat and stirred the mixture	UV/Vis, DLS, SAED, (SAED), SEM, TEM, and XRD	Triangular, hexagonal and spherical (10 nm – 20 nm)	α-amylase and α-glucosidase activity increased from 45 ± 0.83 to 93 ± 1.09 and 57 ± 1.35 to 80 ± 1.54, respectively as dose of increased 10 to 75 μg/ml, respectively	(191)
E. thyrsoideum	Whole plant extract	AgNPs	Plant extract, 15 mL of AgNO3, NaOH solution, centrifugation at 12000rpm, color changed yellow to light brown and then dark brown	FT-IR, UV/Vis, XRD, EDX, SEM, and TEM	Spherical shape (10 nm)	Fasting blood sugar (FBS) decreased in diabetic rats receiving AgNPs on the 7th and 15th days	(192)
C. tomentosum	Leaf extract	AgNPs	5 g of dried leaf, 20 mL of distilled water, 10 mL of AgNO3 and color changed light green to dark brown	UV/Vis, FTIR, XRD, and EDX	Face centered cubic shape	α-amylase and β-glucosidase are 19% and 50%	(193)
S. enterica	Cultural filtrate	AgNPs	AgNO3, centrifugation, stirring (12hrs), color change confirms the synthesis of NPs	UV/Vis, FTIR, SEM, TEM, and EDX.	Spherical shape (7.18–13.24 nm)	AgNPs (3 mL) used and IC50 value of α-amylase and α-Glucosidase are 428.60 and 562.02 μg/mL, respectively	(194)
S. glabra	Rhizomes extract	AuNPs	Plant extract, aq. chloroauric acid (10 mL) solution and dark conditions.	UV/Vis, XRD, SEM, TEM, EDX and FT-IR	Hollow shaped (50-90 nm)	Diabetic rats treated with (50 mg/Kg) and 170 mg/Kg blood glucose reduced	(195)
N. sativa	Seed extract	AuNPs	Extract, chloroacetic acid, stirring, centrifugation at 12000rpm, color changed pale yellow to purple	SEM, TEM, and FTIR	Spherical or triangular shape. Average size (32.96 ± 5.25 nm)	Percentage inhibition of α-amylase and α-glucosidase with 500 µg/mL are 81% and 82.3%, respectively	(95)
P. tortuous	Aerial parts	AuNPs	0.05 mL hydrogen tetrachloroaurate (III), 4 mL plant extract and color changed from yellow to pink	UV/Vis, TEM, XRD, FTIR, and TGA	Spherical, hexagonal and triangular (20–40 nm)	IC50 value of α-glucosidase = 77. 44 mg/mL	(196)

7. Anticancerous potential of Au/AgNPs

The MTT test was performed to investigate the in vitro anticancer activity of the synthesized AgNPs, AuNPs, and aqueous leaf extract of Bauhinia tomentosa exhibited IC₅₀ values for lung A-549 cell lines; 28.125, 46.875, and 50 μg/mL and for MCF-7 cell lines 62.5, 23.4, and 13.26 μg/ mL, and HEp-2 cell lines; 103.125, 34.375, and 53.125 μg/ mL, respectively (140). The nanoparticles used to check the cytotoxicity of cell lines HepG2, MDA-MB-231, and MCF-7 were kept alive in a 5% CO₂ and 37°C in CO₂ incubators. However, AuNPs is found with higher cytotoxic probability having IC₅₀ value ranged between 9.20 and 21.46 µg/mL in contrast to bimetallic (Ag-Au NPs) having IC₅₀ value ranged from 37.22 to 49.94 µg/mL. However, the cytotoxic potential of AgNPs was not observed up to 60 µg/mL against all cell lines (141). Nanoparticles prepared using A. hirsutus leave extract and effective conjugation of activated folic acid (FA) and chlorambucil (CHL) to AuNPs produced AuNPs-FA-CHL. IC₅₀ value of AuNPs-FA-CHL on cancerous (RKO, HeLa, and A549) and normal cells was 170 and 130 g/mL, respectively. However, using lowered concentrations of AuNPs–FA–CHL is found to have higher anti-cancerous ability than CHL or AuNPs (200). Cytotoxic potential of the gold nanoparticles from Marsdenia tenacissima (2.5–25 ug) in prostate cancer A549 cell and following the treatment, 20 mL of a dye combination containing ethidium bromide and acridine orange was applied to the well plates. After that, a fluorescent microscope was used to analyze the cells utilizing green and red fluorescence. The IC₅₀ of AuNPs was 15 ug/mL. While at 25 ug/mL cell viability was only 25% (142). Different cell lines, such as PBL, Jurkat (human acute myeloid leukemia), K562 and DL cells, were exposed to AuNPs. The AuNP-exposed Jurkat cell viability significantly decreased by 45.1% to 87.2% at 5-50 ug/mL doses. In the cases of K562 cells, viability was significantly decreased by 38.38% and 50.165% at 25 and 50 μg/mL doses while it was observed 28.51% and 48.16% for DL cells, respectively. On the other hand, no significant reduction of PBL viability was noted with doses of AuNPs up to 25 μg/mL (143). Anticancer potential of AuNPs was observed by cytomorphological alterations of the cancer cell using optical microscopy, which disclosed that AuNPs induce the caspase-independent apoptotic route of cell death. The maximum cell mortality of 80%, 92%, and 98% was observed for Caov-4, MCF-7, and HeLa cancer cells, respectively, using 20 µg mL⁻¹ ethanolic AuNPs for 72 hrs, while for aqueous extract it was 76%, 77%, and 84% respectively (144). To evaluate the cytotoxic effects of nanoparticles by the MTT assay synthesized by C. guianensis, HL-60 cells were used. They were supplemented with 2 mg/L of NaHCO₃, 4.5 mg/L of glucose, 100 mg/L each of streptomycin sulfate, gentamycin, and penicillin, as well as 10% of half-inactivated fetal calf serum in a humid environment with 5% CO₂. AuNP flower extract in a concentration-dependent manner showed the (cytotoxicity concentration) CC₅₀ value of 5.14 μM whereas for PBMC it was 113.25 μM (145). Gold and silver nanoparticles using Dendropanax morbifera leaf had little to no cytotoxic impact on HaCaT and cancer cells but had a greater synergistic effect on A549 lung cancer cells. The results indicated that D-AgNPs exhibited less cytotoxicity in the human keratinocyte cell line at 100 µg/mL after 48 h while potent cytotoxicity in the lung cancer cell. However, both D-AgNPs and D-AuNPs at 50 µg/mL enhanced the cytotoxicity of ginsenoside compounds at 25 µM after 48 h of treatment as a compared compound alone (146). Solanum xanthocarpum extract was used to synthesize AuNPs and cell viability was checked by MTT assay. Control C666-1 cells (100% viability) treated with NPs exhibited a round morphology and decreased in the formation of colonies found using different concentrations of 5, 10, and 15 µg/mL but just 20% colony formation was reported at high concentrations (147). AuNPs cytotoxicity toward SKBR3 was compared to that of anticancer drugs using the MTT test in a dose-dependent manner. The anticancer compound with its varying concentration 10–40 µg/mL along with the same nanoconjugate concentration was applied and higher antiproliferative effects were observed. Cell viability was 30% in conjugation while alone it was 45% at the concentration of 40 µg/mL followed by 60% and 80% at 20 µg/mL, which might be due to higher uptake of the complex mixture in nucleus or cytoplasm functionalized AuNP carrier (148). The MTT test on a lung cancer cell line (A549) was used to evaluate the anticancer effects of nanoparticles, signs of cell shrinkage found, and the sample inhibits cancer cell growth in a dose-dependent way. IC₅₀ values of Indigofera tinctoria leaf extract, AgNP-tinctoria, and AuNP-tinctoria, respectively, were 71.92 ± 0.76 ug/mL, 56.62 ± 0.86 μg/mL, and 59.33 ± 0.57 μg/mL (149). The ability of AuNPs to stop the proliferation of AGS cells and biocompatibility with rBM-MSCs was assessed. The metabolic activity was to be reduced by AuNPs for cancerous cells and normal cells beyond 10 ppb and by 25 ppb, respectively. AGS cell line treated with AuNPs for 24-72 hrs and MTT assay depicted a significant dose-dependent reduction in metabolic activity of 25–100 μg/mL. The normal cells (bone marrow-derived mesenchymal stem cells) were incubated with AuNPs and a reduction in metabolic function beyond 25 μg/mL was observed (150).

Cell viability was studied on cervical carcinoma using MTT assay and synthesized AuCuO NPs 25 (μg/mL) was further evaluated as potential anticancer agents in HeLa cells. The IC₅₀ values for CuO, Au-CuO nanomaterials, and the control drug (5-fluorouracil) were 12.3, 112, and 40 µM, respectively (152). AuNPs with crocin embedded are effective against breast cancer cell lines using the MTT test. The IC₅₀ values of crocin-AuNPs after 24 and 48 hrs of incubation were reported 1.8 ± 0.08 mg/mL and 1.2 ± 0.04 mg/mL, respectively (153). Musa acuminata flower-based AuNPs and AgNPs were tested against anticancer activity by MTT using 200, 100, 50, 25, 12.5, 6.25, and 3.12 µg/mL concentrations. Normal vero cell line 50% viability was calculated as 55.0, 37.5, 27.5, and 35 µg/mL for AuNPs, aqueous, ethanol, and AgNPs, respectively (154). NPs in varied quantities were applied to the MCF-7 cells. The human breast cancer cell showed 60% cell death at 120 µg/mL concentrations of AuNPs (155). Cytotoxicity study of the synthesized AuNPs exhibited the growth inhibitory property at the concentration (GI₅₀) 40 of 257.8 μg/mL in human adenocarcinoma breast cancer (MCF-7) cells after 48 hrs (156). Stigmaphyllon ovatum leaf extract-based AuNPs were synthesized to reveal cytotoxic effects toward the growth of the HeLa cell carcinoma cells with IC₅₀ values of 5.75 × 10⁻¹⁶ µM, 9.1 × 10⁻⁹ and 0.0027 µM for the Ag-Au BNPs, AgNPs and AuNPs, respectively in contrast to the standard drug, 5-fluorouracil with an IC₅₀ value of 40 µM (157). Catharanthus roseus and Carica papaya and the combination of these two extracts (CPCRM)-based AuNPs were used against the cell death of MCF-7 and HepG2 cells that gradually increases as the concentration increases. Doxorubicin (250 g/mL) was used as a positive control and significantly cell death was found at about 97.5% and 98.1% against MCF-7 and HepG2 cells, respectively (161). Peripheral blood mononuclear cells (PBMC), the MCF-7 cell line, and control cells were placed in 24-well plates, and left to incubate for 24 hrs. Cell viability of 80.3% and 71.5% against PBMC cells and MCF-7 cells was seen at 100 μg. The IC₅₀ values for PBMC and MCF-7 cells were about 600 and 6 µg/mL, respectively (162). The MTT test was used to determine the cyto-survival assay using pure verbascoside- and VB-loaded gold nanoparticles in a medium containing 2% fetal bovine serum and the cell survival rate was 80%, 70%, and 57% for AuNPs, VB, and Au-VB, respectively. According to in-vivo investigation, VB-Au significantly slowed the growth of mouse tumors and caused the tumor cells to die (201). Rosa damascene-based AuNPs (50 and 100 μg/mL) were used against A549 and HL60 cells to check cell viability which was determined after 72 hrs and the cell viability was reduced by almost 22% and 33% against A549 and HL60, respectively. The cytotoxicity effects toward HL60 cells (acute leukemia) are more sensitive than those of the A549 (adenocarcinoma) cells within the same test concentrations and incubation times which demonstrated that the nanoparticles activity was dose-dependent (164). The anticancer potential of the polymer-based nanoparticles (PCL-F68-D-NPs) was evaluated using in-vitro models (202). The green synthesis of gold and silver particle from different biological sources along their anticancer activity has been documented in Table 3.

Table 3. Green synthesis of silver and gold nanoparticles and their anticancer activity.

Green Source	Source part Extract (Leaves, stem, roots)	Type of NPs (Au/Ag)	Method/Reaction Conditions	Characterization Technique	Size of NPs	Anticancer activity	Reference
Z. officinale and C. amada	Sprout extract	AgNPs	Aqueous sprout extract (30 mL), Silver acetate (70 mL of 0.1 M), and centrifuged at 5000 rpm	UV/Vis, FTIR, SEM and XRD.	Spherical(25-30 nm)	Human colon carcinoma cells (HCT15), Cell viability of Z. officinale AgNPs (500 µg/ml) = 43.71% and IC50 = 96.73 μg/mL and C. amada AgNPs (500 µg/ml) = 49.49% and IC50 = 103.66 μg/mL	(179)
C. sativa	Leaf extract	AgNPs	AgNO3 (1–10^–3 M), Plant extract (20 mg/mL) and stirring for 12 hrs at 25 ^OC	UV/Vis, FE-SEM, TEM, and FTIR	Spherical shape (11.5 nm)	IC50 value against WiDr cell line = 379 mg/mL, SW-1417 cell line = 285 mg/mL, DLD-1 cell line = 377 mg/mL, LS123 cell line = 350 mg/mL, ATRFLOX cell line = 241 mg/mL, Caco-2 cell line = 296 mg/mL	(181)
T. indica	fruit shell	AgNPs	Plant extract (400 mL), AgNO3 (10 mM), double distilled water (1000 mL) + stirring for 2 hrs at 45°C	UV/Vis, SEM, TEM, XRD, and EDX.	Spherical shape (20–52 nm)	Breast cancer cell line: IC50 = 20 μg/mL	(203)
C. behen	Leaf extract	AuNPs	Plant extract (20 mL), HAuCl4 solution (100 mL), red color appearance, Centrifugation at 8880 rpm for 10 mins	UV/Vis, TEM, XRD, and EDX	Spherical shape (20–50 nm)	Leukemia cell line: IC50 = 25 μg/mL	(204)
C. versicolor and B. edulis	Mashroom extract	AgNPs	AgNO3 (25 mL), Microwave at 475W for 2 mins, Centrifuge for 10 mins at 20,000 rpm	UV/Vis, DLS, and FTIR.	Average size of CV-AgNPs and BE-AgNPs were 86.0 ± 3.8 nm and 87.7 ± 0.8 nm	IC50 value of CV-AgNPs: MCF-7 = 34.37 ± 0.74 μg/mL, HT-29 = 13.24 ± 0.10 μg/mL, HUH-7 = 13.24 ± 0.10 μg/mL. IC50 values of BE-AgNPs for MCF-7 = 8.48 ± 0.13 μg/mL, HT-29 = 8.00 ± 0.78 μg/mL and HUH-7 = 3.59 ± 0.86 μg/mL	(205)
L. usitatissimum	Flaxseed extract	AuNPs	Seed extract (6 mL), HAuCl4 10^−3 M and color changed to ruby red	UV/Vis, XPS, FTIR, XRD, EDX, and TEM	Spherical and triangular morphology (3.4–6.9 nm)	IC50 value of FS-AuNPs for MCF-7 = 9.9 µg/mL, HepG-2 = 14.5 µg/mL and HCT-116 = 17.9 µg/mL	(206)
F. persica	Aerial parts	AgNPs	Extract solution (25 mL), NaOH (0.2 mM), AgNO3 (8 mM), stirring for 60 mins at 65°C, color changed to dark brown and centrifuged for 15 mins	SEM, TEM, EDS, XRD, FTIR, and UV/Vis	Spherical shape (15 nm)	IC50 value of Fp-NPs for MCF-7  = 21.28 µg/mL and Fp-NPs for AGS cell line = 11.07 µg/mL	(207)
A. strains	Supernatant of fungi spores	AgNPs	AgNO3, supernatant (1 mM), pH = 8.5, Store in dark chamber, Color changed from pale yellow to dark brown	UV/Vis, FTIR, TGA, TEM, EDX, and XRD	Spherical shape (18.99 nm size)	IC50 value of Fp-NPs for A549 = 31.41 g/mL	(208)
S. barbata	Whole plant	AuNPs	Aqueous Extract plant (10 mL), chloroauric acid (0.1 M), stirring for 3 hrs, Centrifugation for 15 mins at 10000 rpm, and color changed from brown to red	UV/Vis, TEM, SAED, AFM, and FTIR	Spherical (154 nm)	Activity of AuNPs against pancreatic cancer cell lines (PANC-1) was decreased as the conc. Of AuNPs increases	(209)
R. rubescens	Leaf extract	AuNPs	Aqueous leaves extract (10 mL), 190 ml of 1 mM Gold (III) chloride trihydrate solution, and color change from yellow to ruby red	UV/Vis, FTIR, SAED and AFM	Poly dispersed (130 nm)	Lung carcinoma A549 cell lines IC50 value of RR-AuNP for A549 = 25 mg/mL	(210)
A. berry (AB) and E. berry (EB)	Fruit extract	AuNPs	Berry extract, deionized water, chloroform, EtOH, heating at 100°C, stirring, 100 mL of 0.1 M NaAuCl4 solution, Centrifuge for 10 mins at 15,000 rpm	UV/Vis, and TEM.	Spherical, triangular, and rod-like shapes. AB-AuNPs (194 nm) and EB-AuNPs (172 nm)	AB-AuNPs cause 41% cell death in Panc-1. EB-AuNPs cause 30% cell death both in prostate PC-3 and pancreatic (Panc-1).	(211)
P. granatum	Peel extract	AuNPs	Peel extract (10 mL), gold chloride (1 mM), stirring, and centrifuge for 10 min at 8000 rpm	UV/Vis, SEM, and EDX	Spherical shape (6 nm)	Cell viability against HepG-2 of Au-NPs at 1 µg/mL = 84.81% while at 100 µg/mL = 16.9%	(212)
T. diffusa	Leaf extract	AuNPs	Leaf extract (1 mL), chloroauric acid solution (9 mL), stirring for 4 hrs, and centrifuge for 10 mins	UV/Vis, SEM, and FTIR	Spherical shape (24 nm).	head-kidney Leukocytes cell lines used. Cell viability of 12.5 μg/ml AuNPs = 130%, 25 μg/ml AuNPs = 120% and with 50 μg/ml AuNPs = 90%	(213)
P. crispum	Leaf extract	AuNPs	Leaf extract (2.5–20 mL), HAuCl4.H2O solution, heated until boil, Stirring for 2 mins and Store NPs at 25 ^OC	UV/Vis, TEM, XRD, EDX, and FTIR	spherical, agglomerated, and deformed shapes (17–50 nm)	Human cancerous colorectal cell line (CO-II) used and IC50 value of Au-NPs = 56.83–84.39 mg/mL	(214)
C. Microphylla	Fruit extract	AgNPs	Fruit extract (12.5 mL) 25 ml of 10 mM AgNO3, washed and dried in oven	FTIR, XRD, EDS, XRD, FESEM, TEM and UV/Vis	Spherical (30 - 50 nm)	IC50 value of AgNPs for AGS  = 34.30 µg/mL and for MCF-7  = 29.02 µg/mL	(215)
L. chinense	Fruit extract	AuNPs and AgNPs	Fruit extract (5 mL), Gold (III) chloride trihydrate for AuNPs, AgNPs solutions and centrifuge for 10 mins at 15,000 rpm	UV/Vis, XRD, and EDX	AuNPs agglomerated (20-100 nm) and AgNPs Spherical shape (50–200 nm)	Cell viability of LC-AuNPs (25 µg/mL) for MCF-7 = 90% and RAW264.7 = 100%. Percentage cell viability of LC-AgNPs (25 µg/mL) for MCF-7 = 60 and RAW264.7 = 80%	(216)
J. auriculatum	Leaf extract	AuNPs	leaf extract (10 mL), HAuCl4.3H2O (1 mM), centrifugation for 20 mins at 10,000 rpm, and color changed from light yellow to violet	UV/Vis, SEM, and TEM	Spherical shape (8–37 nm)	Human cervical cancer cell line IC50 value of AgNPs = 104 μg/mL	(217)
T. polium	Leaf extract	AgNPs	Leaf extract (10 mL), AgNO3 (1Mm), and stirred at 25°C for 30 mins	UV/Vis, XRD, SEM, and FTIR	Spherical shape (70–100 nm)	IC50 value of Ag-NPs against human gastric cancer cell MNK45 = 68.2 μg/mL	(218)
N. crenulata	Leaf extract	AgNPs	AgNO3 (47.5 mL), ultrasonic water bath at 35°C for 30 min, and centrifuge for 20 mins at 4000 rpm	UV/Vis, XRD, FT-IR, SEM, and AFM	Spherical (20–40 nm)	IC50 value of Ag-NPs against breast cancer (HER2) = 72.88 μg/mL	(219)
H. spinosa	Whole plant extract	AuNPs	Aqueous HAuCl4 hydrate solution, plant extract, centrifuge for 10 mins at 10,000 rpm, and centrifugation of collected supernatant for 1 h at 14,000 rpm	UV/Vis, FTIR, XRD, TEM, FEG-SEM, and EDS	Spherical, polygonal, rod and triangular shapes (68.44 ± 0.30 nm)	Cell viability of AgNPs against MCF-7 = 43.78%, MB-231 (breast) = 39.34%, U-87 (brain) = 27.89%, SKOV-3 (ovarian) = 21.45% and NCI/ADR = 31.48%	(220)
P. tuberosa	Flower extract	AuNPs	Floral extract (3 mL), HAuCl4 (1.5 mM), pH = 9, and Temperature 60°C	UV/Vis, FTIR, XRD, and TEM	Spherical in shape (38.76 nm)	IC50 value of Au-NPs against MCF-7 = 100 µg/mL	(221)
D. viscosa	Leaf extract	AgNPs	Leaf extract (5 mL), AgNO3 (1 mM), buffer (2.5 mL) and magnetic stirring for 2 hrs	UV/Vis, FT-IR, XRD, HR-SEM with EDX and HR-TEM	Worm-like, irregular flower, spherical, and dendritic shapes (12-20 nm)	A549 lung cancer cell lines used and IC50 value of worm-like NPs = 14 μg/mL, flower-like NPs = 3 μg/mL, spherical-like NPs = 80 μg/mL and spherical-like NPs = 4 μg/mL	(222)
T. glandulosolanosa	Leaf extract	AgNPs	AgNO3 (0.5 mM), leaf extract, Stirring and Centrifuge for 15 mins at 12,500 rpm, washing with water, and dried for 48 hrs at 40°C	UV/Vis, DLS, SEM and TEM	Quasi-spherical (6.64–51.00 nm)	Cell viability of AgNPs against MCF-7 = 42.70%, A549 = 59.24% and L929 = 8.80%	(223)
A. halimus and C. amperosidies	Whole plant extract.	AuNPs	Plant extract (10 mL), HAuCl4.3H2O (0.011 M), Color changed from golden yellow to violet	UV-Vis, FTIR, XRD, EDX	Spherical shape Atriplex halimus (2-40 nm)	Cell viability of halimus-AuNPs = 35.64 lg/mL against MCF-7 and for C. amperosidies-AuNPs = 38.46 lg/mL	(224)

Gold and silver nanoparticles have received a lot of attention in cancer research due to their distinctive physicochemical properties and potential anticancer activities. Examples of typical mechanisms include the induction of apoptosis, or a method for planned cell death, by gold and silver nanoparticles, which have been studied (225). These nanoparticles can activate signaling pathways, which in turn induce caspases to activate, break DNA, and ultimately lead to the controlled death of cancer cells (226). Both gold and silver nanoparticles have the ability to produce reactive oxygen species (ROS) inside cancer cells (227). Oxidative stress, which is brought on by elevated ROS levels and damages cellular components such as proteins, lipids, and DNA, can lead to apoptosis or other forms of cell death.

Gold and silver nanoparticles can interfere with mitochondrial activity, reducing energy output and triggering the release of pro-apoptotic proteins (228). According to certain research, autophagy, a cellular process involved in the breakdown and recycling of cellular components, may be modulated by gold and silver nanoparticles. Particularly, the ability of gold nanoparticles to prevent angiogenesis is the growth of new blood vessels that feed tumors (229). The immune system may interact with gold and silver nanoparticles, changing the tumor microenvironment. Gold and silver nanoparticles’ functionalization with organic moieties improves distinctive surface characteristics enabling them to interact with targeted ligands. As a result, the nanoparticles can more effectively transport drugs to cancer cells while delivering less damage to healthy cells (230).

8. Challenges and future perspectives of green synthesis of NPs

The use of silver and gold nanoparticles as potential anticancer and antidiabetic agents holds promise, but there are several challenges and future perspectives that need to be considered. One of the primary challenges is ensuring the biocompatibility of silver and gold nanoparticles. While these nanoparticles exhibit therapeutic potential, their interactions with biological systems need to be carefully studied to avoid any toxicity or adverse effects. The efficient and targeted delivery of nanoparticles to specific cells or tissues remains a challenge. The development of strategies to specifically target cancer cells or diabetic tissues while minimizing off-target effects is crucial for effective therapeutic applications. Silver and gold nanoparticles can be prone to aggregation or instability in physiological conditions. To maintain their stability and preventing unwanted aggregation during storage and administration is important for ensuring their efficacy. The understanding of pharmacokinetics and bio-distribution of nanoparticles is essential for optimizing their therapeutic use. Factors, such as their size, surface properties, and clearance mechanisms, influence their distribution in the body and affect their efficacy. The introduction of silver and gold nanoparticles as therapeutic agents requires rigorous safety evaluation and regulatory approval. Demonstrating their efficacy and safety through preclinical and clinical studies is essential for their translation into clinical practice.

Silver and gold nanoparticles can be used in combination with existing therapies to enhance their efficacy. For example, nanoparticles can be used as drug delivery vehicles to improve the delivery and bioavailability of anticancer or antidiabetic drugs. To explore the synergistic effects of silver and gold nanoparticles with other therapeutic agents, such as natural compounds or other nanoparticles, may enhance their therapeutic potential. Combined treatments can potentially provide complementary mechanisms of action and improved outcomes. To tailor nanoparticle-based therapies to individual patients based on their unique genetic, molecular, or physiological characteristics could improve treatment outcomes. Personalized medicine approaches may involve nanoparticle formulations specific to patient subgroups or the use of nanoparticles for the targeted therapy. The advancements in characterization techniques, such as imaging modalities and spectroscopic methods, can provide valuable insights into the behavior and interactions of nanoparticles in biological systems. This knowledge can contribute to the optimization of nanoparticle-based therapies. The development of biodegradable or bioresorbable nanoparticles can address concerns related to long-term accumulation and potential toxicity. Biodegradable nanoparticles can be designed to degrade or be eliminated from the body after exerting their therapeutic effects. In summary, while there are challenges associated with the use of silver and gold nanoparticles as anticancer and antidiabetic agents, ongoing research, and advancements in various areas hold promise for their future applications. To understand the effects of temperature, concentration of the reducing agent, light, time, etc., on the synthesis of AuNPs, several tests must be carried out to optimize the synthesis of nanoparticles. The interaction and quadratic impacts of the different variables should be taken into account throughout the optimization process. Additionally, there are still unanswered problems regarding chemical composite knowledge and the process underlying the transformation and stability of AuNPs during bio-reduction. To address the mechanism of AuNP synthesis and its impact on the shape and size of AuNPs for a variety of applications, more studies and analyses are needed of this era.

9. Conclusions

Medicinal plants are rich source of the different bio-active compounds which can be used in the bio-synthesis of metallic nanoparticles by green approaches. With increasing the population of the global, diseases are also increasing with rapid speed and curing such disease in a challenge to the medicinal chemist. The green synthesis is more safe, more secure, and more economical than other approaches. Among the metallic nanoparticles, silver and gold are most studied due to their great potential for anticancer and antidiabetic. These nanomaterials have even comparative results toward the standard drugs. The exact mechanism about the mode of action for diabetic or cancer is still needed in detail.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The Authors acknowledge the support and funding of King Khalid University through Research Center for Advanced Materials Science (RCAMS) under grant no: RCAMS/KKU/002-23.