The implementation of nanoparticles (NPs) for the treatment and diagnosis of disease is a revolutionary concept that has been developed over the past few decades. The nanotechnological approach can be divided into two branches: one is nanodevices and the other is nanomaterials. The nanodevice can be defined as such tiny devices at the nanoscale range, which includes microarrays and some devices such as respirocytes ^[1][2][3][1,2,3].

Particles smaller than 100 nanometers (nm) in any one of the dimensions are considered nanomaterials. Biomedical science found successful result by using nanoparticles as therapeutic agents in the treatment of various diseases. As it is selective on the target organ and receptors, it overcomes several limitations of conventional therapy, such as nonspecificity, unwanted side effects, less efficiency, and low bioavailability [4].

Therefore, current research projects are considerably more focused on developing and designing new drug delivery systems, and the most promising area is ensured by NPs for their uniqueness in biological and physicochemical characteristics, as they can deliver molecules to specific locations in the body [5].

The therapeutic molecules which are insoluble in water can be complexed with NPs, resulting in greater bioavailability and significantly fewer physiological barriers; for example, NP carriers assist medication in passing the blood–brain barrier (BBB) ^[6][7][8][6,7,8]. Nevertheless, because it is targeted, it will require lower doses than conventional therapy, and the therapeutic index will be higher as it will minimize the toxicity in the biological system. The utilization of NPs in various fields of the health sector is possible because of their ability to provide a visual image of the targeted delivery location by using some agents; moreover, their pathway can be tracked.

Several studies have recently focused on the method of producing metal NPs using green synthesis, which has shown positive results against pathogens, cancer cells, helminths, fungi, etc. using the metal NPs Zn, Ag, Au, Pt, Mn, Ni, and Ti [9]. Currently, among other NPs, Ag-NPs are one of the top listed compounds being researched [10]. In 1857, Michael Faraday was the first person to study Au-NPs in a colloidal system and report Au-NP’s optical features [11].

2. Therapeutic Applications of Metal NPs

2.1. Therapeutic Interventions of Gold Nanoparticles (Au-NPs)

When Robert Koch discovered that gold cyanide had a bacteriostatic effect on Mycobacterium TB, the medical use of gold for the treatment of tuberculosis was established for the first time. This led to the introduction of gold as a medicine in the 1920s ^[12][110]. Au-NPs have a tendency to aggregate at tumor sites ^[13][95]. Tumor cells can be killed by Au-NPs in a variety of ways, including as drug delivery systems for mechanical damage, anticancer medicines, and photothermal ablation ^[14][111]. In particular, Au-NPs are used in drug delivery, imaging, photo-thermal therapy, sensing, catalysis, and antimicrobials ^[15][112]. The list of applications of Au-NPs is much longer because of their unique properties. The biocompatibility of gold nanoparticles has been well documented; however, the typical reduction procedures used to create them can leave behind harmful chemical species ^[16][113]. Consequently, Au-NPs manufactured in an environmentally friendly manner hold far more promise in a variety of settings. Although Au-NPs are not as widely used as Ag-NPs as antibacterial agents, they nonetheless have considerable impact against a wide range of diseases due to their inherent biocidal qualities ^[15][17][112,114]. Au-NPs of 60 nm showed a positive result in retinoblastoma treatment ^[18][115], Au nanopopcorn 28 nm in size is used to diagnose prostate and breast cancer ^[19][116], and Au nanostars (Au-NS) 30 and 60 nm in size can be used to identify brain tumors, and this same NP showed a satisfying result against bladder cancer ^[20][117]. Silica-coated Au nanorods showed effective antitumor activity, both in vivo and in vitro, against breast cancer by targeting CD44+ receptors ^[21][118]. Colloidal Au-NPs are of interest as nontoxic carriers for drug delivery ^[22][23][24][119,120,121]. In a study, it was found that the internalization of the 50 nm spherical gold nanoparticles (AuNPs) was the best of all the nanoparticles investigated ^[25][122]. TrxR (thioredoxin reductase) function can be inhibited by gold compounds, which causes tumor cells to accumulate reactive oxygen species (ROS) and experience oxidative stress, which ultimately kills the tumor cells ^[26][27][123,124] and the proposed anticancer mechanism of Au-NPs is illustrated in Figure 1.

• Nanotherapeutic Application of Gold

2.2. Therapeutic Interventions of Silver Nanoparticles (Ag-NPs)

Silver has excellent physicochemical features, such as catalytic, optical, electric, and, of course, antibacterial capabilities, and these qualities make silver nanoparticles the most marketable nanoparticles. In the presence of Ag-NPs, the synergistic impact of antibiotics such as cefotaxime, azithromycin, cefuroxime, chloramphenicol, and fosfomycin against E. coli was greatly boosted as compared to antibiotics alone ^[30][80]. Other metal NPs may exhibit equivalent efficacy against particular germs, but overall, silver is said to be the most effective material against a variety of pathogens. Ag-NPs inhibit the extracellular activity of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) ^[31][154]. Ag-NPs are the preferred metal when antibacterial characteristics are required. The antibacterial, antiviral, antioxidant, and anticancer characteristics of silver are well recognized, and it has the potential to be developed into a unique therapeutic agent. Ag also has antiparasitic, antiviral, and anticancer qualities ^[32][33][155,156], and the mechanisms of action of these effects are illustrated in Figure 2. Ag-NPs, after entering cells by endocytosis, produce ROS that damage the endoplasmic reticulum and mitochondria. The cellular pathways NF-kB, PI3K/AKT/mTOR, Wnt/beta-catenin, MAPK/ERK, and ERK activation result in DNA fragmentation, cell cycle arrest, and cell apoptosis ^{[34][35][36][37][38]}[157,158,159,160,161]. 

• Nanotherapeutic Application of Silver

2.3. Therapeutic Interventions of Copper Nanoparticles (Cu-NPs)

Researchers and health care professionals have been drawn to cupric oxide (CuO) NPs for their physical, chemical, high temperature, and photocatalytic capabilities, but most notably for their antibacterial properties ^[39][185]. Copper nanoparticles’ synergistic activity with amoxicillin, ampicillin, ciprofloxacin, and gentamicin against both Gram-positive and Gram-negative bacteria was investigated, and ampicillin showed comparatively improved activity compared to alone ^[40][186]. Cu-NPs inactivate glycosidase to provide an antidiabetic effect, and the study found that Cu-NPs showed an anticancer effect by activating BAX and p53 and by decreasing Bcl-2 expression, which result in apoptosis in cancer ^[41][187]. Cu-NPs increase ROS production in bacterial cells and cause bacterial DNA and protein destruction; on the other hand, accumulation of Cu-NPs in the bacterial cell wall causes cell wall disruption ^{[42][43][44][45][46][47][48]}[188,189,190,191,192,193,194]. The mechanisms underlying these effects are depicted in Figure 3.

• Nanotherapeutic Application of Copper

2.4. Therapeutic Interventions of Zinc Nanoparticles (Zn-NPs)

Zinc is a material that is frequently used in biomedical applications due to its unique features, such as electric conductivity, optical capabilities, and piezoelectric qualities ^[49][207]. Beyth et al. defined the method of killing bacteria using zinc oxide (ZnO) NPs as having two pathways of action ^[50][208]. The first involves cell wall penetration, and the second includes the formation of ROS. Zn-NPs follow the Bcl-2/BAX/BAK pathway to cell apoptosis by caspase-3 and -9 and ROS-induced DNA fragmentation leading to cell cycle arrest and apoptosis, and also follow the mitochondrial disruption for an anticancer effect ^[51][52][53][209,210,211], as shown in Figure 4. ZnO-NPs have antibacterial, antifungal, anticancer, antidiabetic, and antitubercular activity, and breast cancer inhibition is an optimistic property that this researchtudy observed in a number of studies. Even 100 nm Zn-NPs supplemented at 30 ppm improved growth and serum glucose levels in layer chicks ^[54][212].

• Nanotherapeutic Application of Zinc

2.5. Therapeutic Interventions of Nickel Nanoparticles (Ni-NPs)

Ni-NPs have anticancer action ^[55][56][260,261]. A complex structure of Qu–PEG–NiGs (48–72 nm), green synthesized by Ocimum sanctum leaf extract, showed mitochondrial-mediated apoptosis against the MCF-7 cell line ^[57][262], antimicrobial activity, antioxidant action, and activity against human ovarian cancer, liver and spleen injury ^{[55][58][59][60]}[260,263,264,265], lung inflammation ^[61][266], human lung cancer ^[62][267], lymphatic filariasis ^[63][268], and larvicidal parasitic activity ^[64][269]. Bacterial protein leakage induced by ROS activation ^[65][270] and disruption of the cell membrane ^[66][271] is one way of causing bacterial cell death. The antimicrobial mechanism is shown in Figure 5. It has numerous other therapeutic properties in a single formulation or a complex formulation.

• Nanotherapeutic Application of Nickel

2.6. Therapeutic Interventions of Iron Nanoparticles (Fe-NPs)

Among the Fe-NPs, prominently used NPs include magnetite (Fe₃O₄), hematite, or iron (III) oxide (Fe₂O₃), and the less abundant iron (II) oxide (FeO) ^[67][281]. Magnetite (Fe₃O₄) NPs are used in biomedical applications due to their magnetic characteristics, biocompatibility, and, in particular, their superparamagnetic capabilities ^[68][282]. Magnetic NPs, also known as superparamagnetic iron oxide, are used in drug delivery ^[69][70][283,284] and hyperthermia therapy ^[71][72][73][285,286,287]. Magnetite NPs can produce receptive oxygen species (ROS), which kill microbes, making them a promising contender for an antimicrobial agent. Lung cancer cells terminated by ferroptosis as a result of Zerovalent Fe-NPs (ZVI-NPs) induce mitochondrial malfunction, intracellular oxidative stress, and lipid peroxidation; here, AMPK/mTOR activated by ZVI-NPs cause upregulation of GSK3/β-TrCP, which results in NRF2 degradation and ultimately results ferroptosis, which causes cancer cell damage ^{[74][75][76][77][78]}[288,289,290,291,292], as shown in Figure 6. Superparamagnetic iron oxide nanoparticles (SPIONs) provide action against the human breast cancer cell MCF7 ^[70][284]. In the treatment of different types of cancer, ferroptosis, a new Fe- and ROS-dependent form of controlled cell death, has received a lot of attention. The potential of ferroptosis in combination with NPs for cancer therapy is becoming more and more clear as a result of the development of nanomaterials ^[79][293]. After cells consume Fe-based NPs, an excess of iron ions released from the lysosome in an acidic environment activates the fenton reaction, which causes ROS formation and cell ferroptosis ^[80][294]. Importantly, when antibiotic drugs are coupled with the iron nanoparticles of neem extract, the dose of traditional antibiotics can be decreased by nearly half without affecting efficiency. As a result, the use of natural antibiotics aids in the reduction of regular antibiotic doses ^[81][295]. There was also a trial of producing bimetallic NPs (Ag-Fe) that established the synergistic antibacterial (bactericidal) impact of the two metals forming the bimetallic nanoparticles when compared to the effects of the monometallic nanoparticles against yeast and both Gram-positive and Gram-negative multidrug-resistant bacteria ^[82][296].

• Nanotherapeutic Application of Iron

3. Metal Nanoparticles Elimination from Body

The elimination of NPs depends on their particle size, intrinsic biodegradability, core density, surface charge, and surface chemistry ^[83][307]. The liver is the major clearance organ in the oral administration of NPs. Intravenously administered NPs are cleared from the bloodstream by two main mechanisms: (i) renal elimination and (ii) hepatobiliary elimination. Choi et al. ^[84][308] reported that smaller-sized (<5.5 nm diameter) quantum dots undergo efficient urinary excretion due to the pore size limit of glomerular filtration in the kidneys. According to estimates of Si-NPs in rats, 7–8% of NPs were eliminated in urine and 75–80% were expelled in feces ^[85][309]. Nonbiodegradable and larger-sized (>5.5 nm) NPs are supposed to be eliminated through the hepatobiliary route. The hepatobiliary elimination involved the following pathways: (1) the liver sinusoid; (2) the space of Disse, a tiny perisinusoidal space containing blood plasma, nutrients, oxygen, and body waste that has become crucial in the treatment of liver disease, which is located between endothelial cells and hepatocytes; (3) hepatocytes; (4) bile ducts; (5) intestines; and finally (6) out of the body, as shown in Figure 7. In hepatobiliary elimination, the liver nonparenchymal cells (e.g., Kupffer cells and liver sinusoidal endothelial cells) influence and determine the elimination fate. The removal of Kupffer cells increased the fecal elimination of NPs by more than 10-fold ^[86][310]. NPs can enter the body through multiple routes, including the skin, respiratory tract, dermal exposure, mucosal, oral, intravenous, subcutaneous, intramuscular, etc., and can induce acute or chronic toxicities ^[87][311]. The anionic NPs are less toxic than the cationic NPs, which cause hemolysis and clotting ^[88][312]. Singh et al. ^[89][313] reported that ceramic NPs, commonly used for drug delivery, exhibit oxidative stress and cytotoxic activity in the lungs, liver, heart, and brain, as well as having teratogenic or carcinogenic effects. NPs have been shown, both in vivo and in vitro, to increase cellular reactive oxygen species, induce multiple minor and severe toxicities, and even disrupt host homeostasis ^[87][311]. Although NPs are useful for numerous medical applications, there are still some concerns for ecosystems and living organisms due to their uncontrollable use and discharge to the natural environment; thus, it should be considered to make the use of NPs more convenient and environmentally friendly. Preclinical studies have revealed the importance of renal-clearable luminous metal NPs in cancer therapy, which offers tremendous promise for potential clinical translation ^[90][314]. The retention of NPs in the body, especially in the vital organs, usually depends on the density of the particles. In a study of gold and silver NPs by Tang et al., it was demonstrated that the lower-density metal NPs have a higher distribution and shorter retention time than the higher-density metal NPs ^[91][315].