1. Introduction

Iron oxides nanoparticle (IONP)-based technologies are catalyzing rapid developments in nanotechnology. Due to technological importance, extensive research has been carried out on the development of various synthetic routes to yield IONPs with desired properties^[1]. Aare chemical compounds which have different polymorphic formong IONPs, mainly Fe₃O₄ aincludindg γ-Fe₂O₃ (marghe extensively studied^[2]. In generalmite), iron oxidFes are classified into different phases ₃O₄ (magnetite), hematite, maghemite, and FeO (wustite). In the nano form, a material possesses interesting optical, magnetic, and electrical properties which cannot be found in their bulk form. This phenomenon can be described as thAmong them, the most studied are γ-Fe₂O₃ "quantum sizd Fe effect"^[3][4][5]. In the nanometer range of I₃ONPs₄, the quantum effect dominates the behavior-affecting magnetic, electric, and optical properties of the matter. In the nanoscale, there is an impact of specific individual atoms or molecules, while in the bulk form, s they possess extraordinary property is attributed to the average of all the quantum forces that affect all of the atoms. For example, magnetic Fe₃O₄ nies at the nanoscale (such anoparticles are supersuper paramagnetic below the size of 20 nsm^[6]., As the nanoparticle size decreases, this property tends towards paramagnetic or superparamagnetic magnetization. Therefore, a decrease in nanoparticle size will enhance superparamagnetic behavior and decrease ferromagnetic behavior. As the size of nanoparticles decreasesigh specific surface area, biocompatible etc.), because at this size scale, the relative oxygen concentration decreases; therefore, a slight reduction in the iron valance state occurs. Because of this ferrous ion content increase, an increase in magnetization should also be observed^[7]. Squantum effects affect matter behavimilaorly, γ-Fe₂O₃ n and oparticles have gained technological importance due to their tical, electrical and magnetic and catalytic properties. High magnetization and hysteretic heating make them potential candidates in separation and biomedical areas, and the semiconducting property and chemically activeTherefore, in the nanoscale, these materials become ideal for surface allow catalytic activities such as photocatalytic ability^[8][9]. Irfunctionalization and modification oxide nanoparticles (IONPs) have a broad range of significantn various applications in electronicsuch as^[10][11], biomsedicine^[12][13][14], enepargy^[15][16], agrticulture^[11][18], aond animal biotechnology^[19][20], as shown technin Figqure 1. In a small size of about 10–20 nm, the superparaes, magnetic properties of Fe₃O₄ sorting (cells and γ-Fe₂O₃ nanoparticles become apparent, therefore, better performance can be achieved for the above-mentioned applications. Additionally, due to theher biomolecules etc.), drug delivery, cancer hyperthermia, sensing etc., and also for increased surfacee area-to-volume ratio, they showwhich allows for excellent dispensarsibility in the solutions^[21].

Figure 1. Various applications of iron oxide nanoparticles (IONPs).

However, reproducible synthesis of IONPs with desired properties is still a probleorm^[22]. Thise is because existing synthesiscurrent methods show a passive approach towards synthesis reaction. The main challenges and key points to overcome them are explained in Figure 2. In existing methods,used are partially and passively mixed reactants are mixed partially and passively. Unreacted components therefore effect the final product when undesired reactions takes place, as the p, and, thus, every reaction has a different proportion of all these factors is different in every reaction, making it which causes further difficult to achieve reproducibility in the desired properties^[23]. Immeies in reprodiate purification of nanoparticles after reaction becomes necessary to minimize errorcibility. Direct active and complete mixing of reactants anand automated approaches could solve this issue. Researchers are mainly focused on be solutions to this size- and shape-controlled synthesis, as size determines the surface area, which playsplaying a key role in its exploitation for scientific or technological purposes^[24].

Figure 2. Challenges and key points in reproducible synthesis of nanoparticles.

2. Manipulation of reaction parameters

Ma An ipulation of reaction parameters is necessary to obtain controlled nanoparticles in terms of size, shape, purity, crystallinity, and morphology. A synthetic route should enabledeal synthesis method should be able to allow reliable adjustment of parameters and control over reaction parameters: temperature; concentration;the following: fluctuation in temperature; pH;, stirring rate; particle distribution; size control; controcentration; and control over shape; nanoparticle e shape and composition and structure, which includes ci.e., crystallinity, purity, and rapid screening, and reliable adjustment of parameters^{[22][25][26][27]}.

I. Iron oxide nanoparticle (IONP)-based available clinical our opinion, the established synthetic routes of iron oxide nanoparticles have difficulty in controlling the particle size, shape, and properties. Many of the reportedapplications are RNA/DNA extraction and detection of infectious bacteria and viruses. Such technologies are important at POC (point of care) diagnosis. IONPs can play a key role in these perspectives. Although there are various methods have their own pros and cons, as described in Table 1. It is necessary to develop a new synthetic route for IONPs that yields nanoparticles in afor synthesis of IONPs, one of the most crucial goals is to control size and properties with high reproducible manner with excellent size control. This review explains various dimensions associated with synthesis of IONPs and their applications, and different synthesis mechanisms are summarized. Figures S1–7 represented in supplementary materials corresponds to various IONPs synthesis methods graphically presented which also includes key points for each corresponding methodility to accomplish successful applications. Using multiple characterization techniques to identify and confirm the oxide phase of iron can provide better characterization capability. It is very important to understand the in-depth IONP formation mechanism, enabling better control over parameters and overall reaction and, by extension, properties of IONPs.

1. Introduction

Iron oxide nanoparticle (IONP)-based technologies are catalyzing rapid developments in nanotechnology. Due to technological importance, extensive research has been carried out on the development of various synthetic routes to yield IONPs with desired properties [1]. Among IONPs, mainly Fe₃O₄ and γ-Fe₂O₃ are extensively studied [2]. In general, iron oxides are classified into different phases (magnetite, hematite, maghemite, wustite). In the nano form, a material possesses interesting optical, magnetic, and electrical properties which cannot be found in their bulk form. This phenomenon can be described as the “quantum size effect” [3–5]. In the nanometer range of IONPs, the quantum effect dominates the behavior-affecting magnetic, electric, and optical properties of the matter. In the nanoscale, there is an impact of specific individual atoms or molecules, while in the bulk form, property is attributed to the average of all the quantum forces that affect all of the atoms. For example, magnetic Fe₃O₄ nanoparticles are superparamagnetic below the size of 20 nm [6]. As the nanoparticle size decreases, this property tends towards paramagnetic or superparamagnetic magnetization. Therefore, a decrease in nanoparticle size will enhance superparamagnetic behavior and decrease ferromagnetic behavior. As the size of nanoparticles decreases, the relative oxygen concentration decreases; therefore, a slight reduction in the iron valance state occurs. Because of this ferrous ion content increase, an increase in magnetization should also be observed [7]. Similarly, γ-Fe₂O₃ nanoparticles have gained technological importance due to their magnetic and catalytic properties. High magnetization and hysteretic heating make them potential candidates in separation and biomedical areas, and the semiconducting property and chemically active surface allow catalytic activities such as photocatalytic ability [8,9]. Iron oxide nanoparticles (IONPs) have a broad range of significant applications in electronics [10,11], biomedicine [12–14], energy [15,16], agriculture [17,18], and animal biotechnology [19,20], as shown in Figure 1. In a small size of about 10–20 nm, the superparamagnetic properties of Fe₃O₄ and γ-Fe₂O₃ nanoparticles become apparent, therefore, better performance can be achieved for the above-mentioned applications. Additionally, due to the increased surface-to-volume ratio, they show excellent dispensability in solutions [21].

Figure 1. Various applications of iron oxide nanoparticles (IONPs).

However, reproducible synthesis of IONPs with desired properties is still a problem [22]. This is because existing synthesis methods show a passive approach towards synthesis reaction. The main challenges and key points to overcome them are explained in Figure 2. In existing methods, reactants are mixed partially and passively. Unreacted components therefore effect the final product when undesired reactions takes place, as the proportion of all these factors is different in every reaction, making it difficult to achieve reproducibility in the desired properties [23]. Immediate purification of nanoparticles after reaction becomes necessary to minimize error. Direct active and complete mixing of reactants and automated approaches could solve this issue. Researchers are mainly focused on size- and shape-controlled synthesis, as size determines the surface area, which plays a key role in its exploitation for scientific or technological purposes [24].

Figure 2. Challenges and key points in reproducible synthesis of nanoparticles.

Manipulation of reaction parameters is necessary to obtain controlled nanoparticles in terms of size, shape, purity, crystallinity, and morphology. A synthetic route should enable control over reaction parameters: temperature; concentration; fluctuation in temperature; pH; stirring rate; particle distribution; size control; control over shape; nanoparticle composition and structure, which includes crystallinity, purity, rapid screening, and reliable adjustment of parameters [22,25–27].

In our opinion, the established synthetic routes of iron oxide nanoparticles have difficulty in controlling the particle size, shape, and properties. Many of the reported methods have their own pros and cons, as described in Table 1. It is necessary to develop a new synthetic route for IONPs that yields nanoparticles in a reproducible manner with excellent size control. This review explains various dimensions associated with synthesis of IONPs and their applications, and different synthesis mechanisms are summarized. Figures S1–7 represented in supplementary materials corresponds to various IONPs synthesis methods graphically presented which also includes key points for each corresponding method.

Table 1.

Merits and demerits of different IONP nanoparticle synthesis methods.