NPs has been recorded as an effective method in combating microbial resistance and multidrug-resistance mutant (Wang et al., 2017) especially on the interaction with microbial biofilm.

Bacterial biofilms are complex surface on the communities of bacteria that consist of microorganism culture, extracellular polymer matrix (EPM), complex biopolysaccharide, secreted protein proteins and extracellular DNA (Muhammad et al., 2020; Shkodenko et al., 2020).

The role of NPs in antimicrobial activity including the disruption of bacterial membranes and interaction with biofilm (Shkodenko et al., 2020). The interaction between NPs and biofilm could occur in following step: transfer of NPs to the biofilm; attachment to the surface and migration into biofilms (Figure 1). The process is affected by physicochemical properties of NPs, the environment and extracellular polymeric matric (Shkodenko et al., 2020).

New approach to combat resistant microorganisms is urgently required to reduce the clinical burden in the use of antibiotics. Nanotechnology-based antimicrobials could be one of strategies which is acting synergistically via intrinsically antimicrobials and those as carriers (Makvandi et al., 2020). Nanotechnology is emerging field of science which deals with the synthesis of nanoparticles in improving physicochemical properties of materials for human benefits (Chau et al., 2022). The success research in nanoparticle-based delivery is due to their advantages such as safety assessment, scalable production, and availability for clinical trials (Hagbani et al., 2022).

The nanoparticles fall between 1 and 100 nm size which can be prepared by top-down methods include mechanical milling, laser ablation, etching, sputtering, and electro-explosion and bottom-up approaches such as chemical vapor deposition, solvothermal and hydrothermal methods, sol–gel method, soft and hard templating methods, reverse micelle methods (Baig et al., 2021). Nanoscale delivery has gained interest due to their exceptional activity allowing reaction to be achieved effectively and efficiently (Baig et al., 2021). Metal-based nanomaterials have been continuously investigated for their application due to their potential usage. Metal nanoparticles (MNPs) display potential capacity and higher surface area making them suitable in numerous applications including medicine, drug delivery, cosmetics, food product, sensors, optics, electronics, paints and agriculture (Perveen et al., 2022).

The metal-based nanocarriers have been reported to increase the antimicrobial activity (Makvandi et al., 2020) in addition to their own activity (Yonathan et al., 2022). The use of noble (magnetic) metal nanoparticles (MNPS) especially gold (Au), silver (Ag) and platinum (Pt) have been attracting great attention due to its multiple antibacterial properties and simple synthesis methods (Shafey, 2020). They act selectively attached to a functional molecule and allow transportation to targeted locations under magnetic fields (Ahmad et al., 2022). The noble metal particle can kill bacteria and eradicate biofilms by cell membrane potential stability disruption as well as binding bacterial enzymes or DNA and (Ye et al., 2022). MNPs can also act as free radical damaging bacterial cell membrane (Ye et al., 2022). Meanwhile, the antibacterial agents show similar mechanisms with one or multiple targets on bacterial protein synthesis, bacterial cell wall synthesis, bacterial cell membrane destruction, bacterial DNA replication and repair as well as inhibition of metabolite pathway (Khameneh et al., 2019). When the antimicrobial agent is encapsulated with metal-nanoparticles, they would have a synergistic effect therefore the toxicity level would decrease and the efficacy would increase.

Metal nanoparticles are becoming a trend strategy to improve antibiotic activity due to its simple synthesis. Antibacterial activity of the antibiotic is different against bacterial gram stain, due to organization of the structures outside the plasma membrane but below the capsule where in Gram-negative organisms these structures constitute the cell envelope, whereas in Gram-positive organisms they are called a cell wall (Salton and Kim, 1996). The silver nanoparticles alone excellently discompose the polymer sub-units of the cell membrane in micro-organisms. In combination with plant material which is mediated silver nanoparticles consequently rupture the cell membrane and destroy the protein synthesis mechanism in the bacteria (Bukhari et al., 2021).

Study on antibiotic colistin on anionic gold nanoparticle against Escherichia coli reduces minimum inhibition of 6-folds compared to colistin alone (Fuller et al., 2020). A gold nanoparticle of vancomycin has shown more effective inhibition towards Gram-negative bacteria of E. coli, Klebsiella oxytoca and Pseudomonas aeruginosa with 1.4, 1.6 and 1.8 folds inhibition and towards Gram-positive bacteria, Staphylococcus aureus with 1.6 fold compared to free vancomycin (Hagbani et al., 2022). Combinatorial silver nanopacked Daptomycin inherits synergistic effects of both for their bactericidal activity (Zheng et al., 2016).

Several methods have been introduced to synthesise metal NPs including chemical, physical and biological methods using microwave-assisted, radiation-assisted, thermal decomposition, chemical and photo-chemical reaction, and green synthesis methods. Synthesis using bio-organisms or green synthesis compatible with the green chemistry principle. And green synthesis is required to avoid the production of unwanted or harmful by-products through the build-up of reliable, sustainable, and eco-friendly synthesis procedures. To achieve the goal of green synthesis, the natural resources and the ideal solvent systems that are environmentally friendly, non-toxic and safe reagent are essential (Singh et al., 2018).

Green synthesis of MNPs synthesised using biological techniques or green technology have diverse natures, with greater stability and appropriate dimension since they are synthesised using a one-step procedure. Therefore, the green synthesis of MNPs has been adopted to accommodate various biological materials, such as viruses, bacteria, fungi, algae, yeast, plant and plant products. Many researchers prefer to use green synthesis due to some advantages including cost effectiveness because the biological component itself acts as reducing and capping agents, eco-friendly approach as toxic chemicals are not used, and external experimental conditions like high energy and high pressure are not required that lead to energy saving process. Furthermore, the synthesis of a wide range of MNPs has been reported using various plants because it is a simple and easy process to produce MNPs at large scale compared to bacteria and/or fungi mediated synthesis (Song and Kim, 2009; Alarjani et al., 2022; Ye et al., 2022).

Plant mediated synthesis of MNPs is a revolutionary technique that has a wide range of applications in medicine, agriculture and food industries that offer an advantage which increases the life span of NPs. This is due to the physico-chemical properties of the plants based MNPs that overcome the limitation of conventional chemical and physical methods of NPs synthesis (Malik et al., 2014; Kalpana and Devi Rajeswari, 2018). Plant mediated synthesis of MNPs can be achieved by three different methods, intracellularly (inside the plant), extracellularly (using plant extracts), and using individual phytochemicals. Plants can mediate the synthesis of MNPs intracellularly because plants have the capability to accumulate the metals and transform these accumulated metals to NPs intracellularly. Moreover, the presence of several biomolecules such as protein, amino acids, carbohydrates, reducing sugar, vitamins, alkaloids, aldehydes, flavones, ketones, phenolics, saponins, tannins, and terpenoids in the plant plays a key role in the reduction of metals. These biomolecules contain hydroxyl, carbonyl and amine functional groups that react with metal ions and reduce their size into nano size. For example, flavonoids contain several functional groups, and it is believed that the -OH group of flavonoids is responsible for the reduction of metal ions into NPs (Marslin et al., 2018; Dikshit et al., 2021). Flavonoids not only help in bio-reduction of the metal ion to the nano size, but also play an important role in the capping of the NPs which is important for the stability and biocompatibility (Javed et al., 2020). In addition, reducing agents such as phenolics, sterols and alkaloids can reduce the metal ions into NPs in a single reaction (Biswas et al., 2013).

The type and nature of the metal used for MNPs biosynthesis mainly determine the NPs end use industry. Several metal such as silver (Ag), copper (Cu), gold (Au) and many others have been widely used for the biosynthesis of NPs using plant extracts of various plant species (Zhang et al., 2020). Au and Ag were the first metal ion used in plant extract-mediated synthesis of NPs. Acalypha indica, Aloe barbadensis, Datura metel, Nelumbo nucifera, Jatropha curcas, Ocimum leaf, Cassia auriculata, and Rhododedendron dauricam have been used to produce Ag nanoparticles. Gold nanoparticles have also been synthesized using Aloe barbadensis Miller, Medicago sativa, Magnolia kobus, Diopyros kaki, Cinnamomum camphora, and Pelargonium graveolens leaf (Jeevanandam et al., 2016).

Peralta-Videa et al., 2016 reported the synthesis of plant based metallic nanoparticles and their potential application. Metals from their constituents are reduced and stabilised by macromolecules and phytonutrients, such as proteins, reducing sugars, phenolics, flavonoids, ethyl alcohols, terpenes, and phenolic acids present in plant extracts. (Naseer et al., 2020) split the function of biomolecules in the formation of NPs as redoxed intermediaries for metals reductions and capped agents for non-agglomeration and post-surface modification of NPs.

In general, the synthesis of MNPs is initiated by mixing the plant biomass/extract with of noble metal salt precursors with biomaterial at a desired temperature and pH. The presence of various compounds of biomolecules act as reducing and capping agents for the synthesis of NPs from its metal salt precursors. The reduction of metal salt precursors to its successive NPs can be initially confirmed by visualising the colour change of the colloidal solution (Kuppusamy et al., 2016; Sriramulu et al., 2020).

The variation in the size, shape, and properties of accumulated NPs can be observed due to the variation in stabilising and reducing potential of biomolecules present in the plant. For example, the formation of gold NPs inside the living plant, alfalfa was reported by (Gardea-Torresdey et al., 2002) when the plants were grown in AuCl₄ rich environment. And in a similar kind of study, (Bali and Harris, 2010) observed the ability of Medicago sativa and Brassica juncea plants to accumulate Au NPs from aqueous solutions of KAuCl₄. The NPs were majorly located in the xylem parenchyma cells while some were also accumulated throughout the epidermis, cortex, and vascular tissue. Several studies reported the synthesis of Ag, Au, Cu, Pt, Cd, Pt, Pd, Ru, Rh, etc. using various biological agents in the recent past. The experimental procedure for the synthesis of NPs using plant biomass is depicted in Figure 2.

The mechanism of action of MNPs on bacterial cells is affected by the physiochemical properties of NPs such as charge, size, zeta potential, surface morphology and crystal structure. Whereas, the environmental factor, exposure time and bacterial strains are also influence the antibacterial effect of MNPs (Wang et al., 2017). There are three well known antimicrobial effects of NPs includes electrostatic interaction causing mechanical damage of cell walls, generation of reactive oxygen species resulting oxidative stress and disruption of cell structures and protein structure as a result of metal release (Wang et al., 2017).

Despite several approaches that have been made over the years, the precise mechanism of action of MNPs as antimicrobial agents is still not fully understood. Antimicrobial action of MNPs is linked to four main mechanisms, attraction to bacterial surface, destabilisation of bacterial or fungal cell wall and/or membrane with change in its permeability, induction of toxicity and oxidative stress by generation of reactive oxygen species (ROS) and free radical, and modulation of signal transduction pathways (Dakal et al., 2016). The adhesion of MNPs onto the surface of bacteria is the first step of a complex mechanism of bacterial inhibition. The adhesion of MNPs is influenced highly by their size and also zeta potential that depends on the method for their synthesis that might have a positive, negative or neutral surface charge. Varying surface charge of MNPs will cause the fluctuation of the antibacterial activity. Since the bacterial surface shows a slightly negative charge, positively charged MNPs are strongly attracted to the surface of bacteria, resulting in an increasing of antibacterial activity. On the other hand, negative or neutral charged MNPs have a significantly decreased antibacterial effect. However, an increase in the concentration of MNPs allows the attenuation of electrostatic repulsion through a bacterial surface saturation method (Abbaszadegan et al., 2015). After the adhesion onto the bacterial surface, MNPs can interact with the cells via two mechanisms, i.e, smaller MNPs penetrate directly into the cell, while the larger MNPs are retained outside the bacteria. In both situations, MNPs continuously release the metal ions, and these ions bind to the cell membrane structure that will destabilise the membrane potential and cause proton leakage. Cell wall destabilisation highly increases bacterial permeability and allows larger MNPs to enter the cell (Losasso et al., 2014).

There are a number of plant extracts and natural compounds isolated from plants that have antibacterial and antifungal activities. Most natural antimicrobial agents that target bacteria appear to disrupt membrane permeability, leading to membrane rupture and cell lysis. Furthermore, the inhibition of ergosterol biosynthesis, reduction of squalene epoxidase activity and fungal cell apoptosis are the specific mechanisms for antifungal, due to the structural differences between bacterial and fungal. However, not all mechanisms of action have been elucidated, and sometimes the mechanism may be indirect, stimulating the host immune system or inhibiting adhesion to the host cell.

Therefore, due to the unique action of metal nanoparticles that working synergically with botanical drugs may be useful to overcome multi drug resistance bacteria. A proposed site of action MNPs in enhancing antimicrobial activity of natural products is shown in Figure 3.

Once inside the cell, MNPs and their metal ions interact with numerous structures and biomolecules such as proteins, lipids and DNA, resulting in cell dysfunction. MNPs are well known by their high capacity to produce ROS and free radicals such as hydrogen peroxide (H₂O₂), superoxide anion (O⁻), and hydroxyl radical (OH^•). Even though ROS occur naturally in bacteria as a result of cellular respiration, under normal circumstances bacteria have defense mechanism such as glutathione (GSH), superoxide dismutase, and catalase that act as antioxidant enzymes and eliminate these toxic species. High concentrations of metal ions released by MNPs produce extreme levels of oxidative stress. However, antioxidant enzymes will remove some of the released metal ions and these are not enough to neutralise ROS and free radical by the MNPs amount (Qing et al., 2018). These species interact with respiratory chain proteins on the membrane and inactivate the enzyme due to their high affinity to phosphates, thiol and carboxyl groups (Gordon et al., 2010). Their linkage to phosphate groups of the enzyme will inhibit the phosphorylation of proteins which is important for enzymatic activation, and this process cause the inhibition of bacterial growth. Furthermore, dephosphorylation of tyrosine residues of protein was also been implicated in disruption of biosynthesis and transport of exopolysaccharide and capsular polysaccharide to the membrane that will cause the disruption of cell cycle (Dakal et al., 2016). In addition, metal ions can intercalate DNA strands forming complexes with nucleic acids between the purine and pyrimidine base pairs that cause the disruption of hydrogen between them (Qing et al., 2018) and cause the DNA damage.

NPs’ physicochemical qualities influence their behaviour, biodistribution, safety, and efficacy. Thus, characterisation of metal NPs is critical for assessing the functional properties of the produced particles. Dynamic light scattering (DLS), zeta potential analyser, scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and UV-vis spectroscopy are some of the examples of technique used for NPs’ characterization. Combining these spectroscopic techniques offers information that could not be obtained with a single approach and helps in determine the quality of the synthesised nanoparticles.

The information such as size, size distribution, shape and surface chemistry are essential since these characteristics affect the absorption of NPs at the targeted site. Size of synthesised metal NPs is usually in the range of 5–100 nm and proven to enhance the antibacterial activity of plant extract loaded in NPs (Anbumani et al., 2022; Deivanathan and Prakash, 2022). The spectroscopy techniques such as DLS usually used to measure NPs size, size distribution and degree of aggregation.

Additionally, zeta potential analyser is used for determining the NPs surface charge. The surface charge above +30 mV and below −30 mV is generally regarded as targeted value to portrays lower degree of NPs aggregation and nanoparticle stability (Samimi et al., 2019). Shape is another NPs characteristic which can be measured using microscopy techniques such as SEM and TEM. TEM for instance, is a common technique to analyse NPs size, size distribution and shape. Other microscopy technique such as AFM can also being used to analyse NPs size, 3D-shape and elemental composition (Mourdikoudis et al., 2018) Usually after NPs synthesis, it will be characterised in terms of their crystal structure and lattice dimension using XRD. This technique was developed primarily to determine the 3D architectures and crystallinity of NPs.

FTIR spectroscopy is a method for determining NP structure and content. This method measures the absorption of electromagnetic radiation in the mid-infrared region (4,000–400 cm⁻¹). FTIR analysis can be performed on both solid and liquid samples, and it has also been used to describe bacteria exposed to nanoparticles. The characteristics of functional groups and metabolites present on the surface of nanoparticles may be easily recognised using FTIR, which can occasionally aid in the reduction and stabilisation of nanoparticles (Nizamov et al., 2022).

UV-visible spectroscopy can be used to examine the scattering and absorption of light travelling through the material. This technique aids in the identification and characterisation of nanomaterials, as well as the determination of the stability of the nanoparticles generated. Other than that, HPLC provides more selective and specific measurement on the encapsulation efficiency, loading capacity and stability of plant extracts in NPs. Figure 4 summarizes the NPs characteristics and techniques used.

The antimicrobial activity of plant extracts loaded in NPs is still unclear, like some are emphasized on bacterial oxidative stress, whereas other NPs such as MgO-NPs may not be associated with bacterial metabolism (Wang et al., 2017). The lack of evidence of mechanism of action of plant extracts itself become a major issue in this review. Another limitation is the complex structure of microorganisms not permitted to be stimulated from in vitro study to in vivo condition. The environmental issue especially to fish and plankton population should be considered another limitation of NPs, due the release of NPs to the environment. The NPs will be ingested by aquatic organisms and be accumulated in animals and further in the food chain (Maharramov et al., 2019).

The combination of two metal or bimetallic nanoparticles in formulation plant extract may increase the antimicrobial activity. The successful bimetallic nanoparticle of Ag-Fe (AgNPs and FeNPs) has been produced using redox reactions of aqueous Gardenia jasminoides. It showed a synergistic effect as bactericidal and fungicidal effects against Gram-positive, Gram-negative and yeast (Padilla-Cruz et al., 2021). On the other hand, the hybrid silver-iron nanoparticle containing aminolevulinic acid showed significant enhancement in their cytotoxic activity on MCF-7 cell lines (de Oliveira Gonçalves et al., 2020). In the case of multidrug resistance, NPs seems to be an alternative strategy to deliver antimicrobial agents to fight numerous antibiotic resistance bacteria.