Magnetic nanoparticles as promising materials for the future of medicine.

Introduction
Recently, there has been a growing interest in nanostructured materials, particularly magnetic nanoparticles (MNPs), within the scientific community [1]. The field of nanotechnology is increasingly recognized for its diverse applications. Historical milestones include Michael Faraday’s pioneering work in the late 19th century, where he synthesized the first gold nanoparticles through the reduction of gold chloride, marking the initial scientific exploration of the optical properties of metal nanoparticles [2]. Extensive research has been conducted on the preparation and synthesis of MNPs to facilitate their application across various domains, including biomedicine, drug delivery, and computing. The design and fabrication of these nanostructures are critical factors influencing their functionality and potential applications [3, 4]. Among the various types of nanoparticles, MNPs stand out as particularly promising tools in the biomedical sector [5]. Their unique properties enable them to serve as effective contrast agents in magnetic resonance imaging (MRI) [6, 7]. Furthermore, MNPs are advantageous for applications such as cell separation, cell tracking, and targeted drug delivery due to their responsiveness to external magnetic fields [8]. Additionally, MNPs have demonstrated potential as agents for antitumor therapy, leveraging their ability to generate heat when subjected to an oscillating magnetic field. This capability enhances their therapeutic efficacy in cancer treatment [9].
Cancer remains a significant global health challenge, with lung and breast cancers being among the most fatal types. Despite the development of numerous anticancer nanomedicines, their clinical performance has often not met expectations, partly due to limited registered medications and suboptimal clinical outcomes [10, 11]. Traditional cancer therapies, such as chemotherapy, radiotherapy, and surgery, although life-saving, are associated with severe side effects and limited efficacy due to issues like non-specific targeting and drug resistance [12, 13]. In this context, MNPs have emerged as a promising alternative, offering a versatile platform for cancer therapy and diagnostics due to their unique magnetic properties and ability to be manipulated by external magnetic fields [14, 15]. MNPs can be functionalized with various therapeutic agents, including chemotherapeutic drugs and antibodies, enabling targeted drug delivery, magnetic hyperthermia (MHT), and photodynamic therapy (PDT), which can enhance treatment efficacy and reduce side effects [16].
Iron oxide nanoparticles (IONPs), in particular, have a long clinical history and are noted for their biocompatibility and effectiveness in deep-tissue imaging and therapy [14]. The small size of MNPs allows them to interact with biomolecules at the cellular level, facilitating targeted drug delivery and magneto-mechanical activation of cell surface receptors [14]. However, challenges remain, such as the limited drug loading capacity of MNPs and potential toxicity issues. To address these, MNPs can be coated with biocompatible polymers or mesoporous silica, which enhance stability, biocompatibility, and drug loading capacity while reducing toxicity [17]. These coatings also prevent nanoparticle agglomeration and allow for the controlled release of drugs, ensuring that therapeutic agents are delivered precisely to tumor tissues without premature release into the body [17]. The integration of MNPs with other nanotechnologies, such as solid lipid nanoparticles, further enhances their potential as theranostic agents, combining therapeutic and diagnostic capabilities in a single platform [15]. Despite the promising preclinical results, translating MNP-based therapies to clinical practice remains challenging, necessitating further research to optimize their design and targeting efficiency [15]. While MNPs offer a novel and promising approach to cancer treatment, ongoing research and development are crucial to overcoming current limitations and realizing their full potential in clinical settings [18–20].
IONPs have a long clinical history, and the numerous clinical products that have been produced because of their use are ignored in many investigations [19]. Even if traditional therapies, including radiation, anticancer medications, and surgery for solid tumors, save lives, they nevertheless have a significant number of negative side effects [21]. MNPs have been used in biomedicine over the past 20 years [22]. They emerged as a brand-new therapeutic option for cancer treatment and MRI. Due to their small size, they can interact easily with biomolecules both inside and outside of cells, enabling the magneto-mechanical activation of cell surface receptors, tissue tagging, targeted drug delivery, and MHT.

Types of magnetic nanoparticles
MNPs are a class of materials that have garnered significant attention due to their unique magnetic properties and potential applications in various fields such as biomedicine, environmental remediation, and data storage. The main classifications of MNPs can be broadly categorized into four types: oxide, metal, shell-functionalized oxide, and shell-functionalized metal [23–25]. Each of these categories has distinct characteristics and applications, which are discussed below.

Oxide magnetic nanoparticles
These are typically composed of iron oxides such as magnetite (Fe3O4) and maghemite (γ-Fe2O3). Oxide MNPs are known for their stability, biocompatibility, and ease of synthesis, making them suitable for biomedical applications like MRI and drug delivery systems. Their magnetic properties are generally weaker than those of metallic nanoparticles, but their chemical stability and non-toxic nature make them highly desirable for in vivo applications [26, 27].

Metal magnetic nanoparticles
These nanoparticles are composed of pure metals such as iron (Fe), cobalt (Co), or nickel (Ni). Metal MNPs exhibit superior magnetic properties compared to their oxide counterparts, which makes them ideal for applications requiring high magnetic responsiveness, such as data storage and magnetic separation. However, they are prone to oxidation and corrosion, which can limit their use in certain environments. To mitigate these issues, metal MNPs often require protective coatings or functionalization to enhance their stability and biocompatibility [18, 28].

Shell-functionalized oxide magnetic nanoparticles
This category involves oxide MNPs that are coated with various materials to enhance their functionality. The shell can be composed of polymers, silica, or other biocompatible materials, which can improve the stability, dispersibility, and functionalization potential of the nanoparticles. These shell-functionalized MNPs are particularly useful in targeted drug delivery and as contrast agents in MRI, where the shell can be engineered to interact with specific biological targets or to carry therapeutic agents [18, 29].

Shell-functionalized metal magnetic nanoparticles
Like their oxide counterparts, metal MNPs can also be coated with protective shells to improve their stability and functionality. The shell not only protects the metal core from oxidation but also provides a platform for further functionalization. This makes them suitable for a wide range of applications, including catalysis, biosensing, and environmental remediation. The choice of shell material can significantly influence the properties and applications of these nanoparticles, allowing for customization based on specific needs [30, 31]. In summary, the classification of MNPs (Table 1) into oxide, metal, shell-functionalized oxide, and shell-functionalized metal categories highlights the diversity and versatility of these materials. Each type offers unique advantages and challenges, which dictate their suitability for different applications. Oxide MNPs are favored for their stability and biocompatibility, while metal MNPs are chosen for their superior magnetic properties. Shell-functionalization further enhances the applicability of both oxide and metal nanoparticles by improving their stability and enabling targeted functionalities. The ongoing research and development in this field continue to expand the potential applications of MNPs, driven by advancements in synthesis techniques and functionalization strategies.

Oxide magnetic nanoparticles
Magnetic oxide nanoparticles, particularly IONPs, have garnered significant attention in the field of medicine due to their unique properties and potential applications. These nanoparticles are primarily composed of iron oxides such as magnetite (Fe3O4) and maghemite (γ-Fe2O3), which exhibit superparamagnetic properties [32, 33]. This means they can be magnetized in the presence of an external magnetic field and demagnetized when the field is removed, making them highly suitable for various biomedical applications. This property, coupled with their customizable sizes, morphologies, and structures, makes them ideal for various biomedical applications. Iron oxides consist of anion arrangements, typically hexagonal or cubic, with partially filled vacancies occupied by divalent or trivalent iron. While tetrahedral coordination is possible, octahedral coordination is more common. The specific arrangement of iron ions within the crystal lattice directly influences the magnetic properties of the nanoparticles. Among the various forms of iron oxide found in nature (including hematite (Fe2O3), magnetite (Fe3O4), and maghemite (Fe2O3)), magnetite is the most prevalent due to its superior magnetic characteristics, stemming from its stable structure and the presence of both divalent and trivalent iron ions [34]. Maghemite, on the other hand, shares structural similarities with both magnetite and hematite, combining elements of their structures and compositions.

Ferrites with a shell
Superparamagnetic iron oxide nanoparticles (SPIONs) have been proposed for medical applications due to their magnetic properties and potential biocompatibility; however, because of the instability of bare magnetite cores, aggregation can occur, making it necessary to take protective steps for surface modifications. A common method of protecting against the negative impacts from aggregation is a dual-layer shell comprised of a biocompatible polyvinyl alcohol (PVA) as the inner layer and SiO2 as the outer layer. This system provides structural stabilization benefits through the PVA, and the outer silica layer provides versatility for functionalization that is required for downstream applications for the diagnostic and therapeutic methods of SPIONs [35–38].
The PVA layer provides more colloidal stability for SPIONs by neutralizing magnetic interactions between nanoparticles. Since PVA is hydrophilic, it also disperses better in aqueous media, which ultimately helps mitigate aggregation in bodily fluids, like blood, thus preserving nanoparticle stability [39]. This is especially important in an in vivo setting where aggregation or agglomeration of nanoparticles can impede circulation, targeting efficiencies, or safety. PVA is also biocompatible and biodegradable and is therefore an appropriate candidate for clinical applications. The SiO2 layer adds additional stability due to its relative inertness toward physiological conditions (other than the size of the nanoparticles), and it also provides surfaces that are chemically modifiable after the SPION cores are formed. In terms of functionalization, this modification occurs readily because the SiO₂ surface can be modified by a ligand, antibody, or other biomolecule for local binding to tumor tissue or some other cell type of interest [40].
The morphology of SPIONs also has an equally meaningful role in their biomedical functionality. Generally, for a successful implementation of MHT in practice, it is necessary to use assemblies of MNPs with a sufficiently high specific absorption rate (SAR) in AC magnetic field of moderate frequency, f < 1 MHz, and amplitude H0 of the order of 100–200 Oe [41]. It has been reported that spherical nanoparticles have been heavily researched; other morphologies have distinct benefits. For example, while cubic SPIONs (~20 nm) demonstrated a significantly higher SAR value of ~450 W/g compared to ~250 W/g for their spherical counterparts under the same AMF conditions (f = 300 kHz, H = 20 kA/m), highlighting their superior suitability for MHT and their higher potential and have a much higher efficiency in heating under alternating magnetic fields (AMFs) than spherical particles, cubic particles could be used as much better candidates for MHT treatments due to their efficient heating especially in lower field strengths, as well as their increased magnetic anisotropy, more favorable surface structure with well-defined lattice planes, and a tendency to form chain-like aggregates, which improve magnetic hysteresis losses. These factors collectively make cubic SPIONs more effective for MHT applications than their spherical counterparts [42, 43]. Further studies also showed an increased contrast in MRI imaging when octopod SPIONs (~30 nm) were used due to greater available surface area with increased magnetic anisotropy. Meanwhile, elongated nanoworm-shaped SPIONs have been shown to accumulate better in tumor sites than spherical SPIONs, putatively due to their morphological design that allows for greater tissue penetration and retention [44, 45]. These studies highlight that when it comes to tailoring nanoparticles for a certain biomedical function, both shape morphologies and surface engineering play a critical role.
From a therapeutic standpoint, most surface coatings around SPIONs help to stabilize SPIONs and decrease the cytotoxicity associated with direct iron oxide core exposure. Surface coatings negatively impact the amount of free iron ions that disperse when PVA and SiO₂ formulations are used to encapsulate SPIONs [46]. This further increases safety when the SPIONs are circulating, as well as informing researchers of iron release when tissues continue to interact for a longer timeframe. Additionally, the SiO₂ layer may act as a reservoir for drugs, allowing for controlled releases of therapeutic molecules in pathological sites. This treatment approach is especially advantageous in oncological settings, when localized drug molecule release minimizes systemic adverse side effects but still achieves significant pharmacological efficacy [47].
Interestingly, dual-shell SPIONs (with a combination of superparamagnetic core and silica shell) can be used in many diagnostics, including as MRI contrast agents. The superparamagnetic core would produce a strong T2-based contrast, while designed materials to functionalize the surface with targeting ligands would yield added specificity to be indicative of histopathological study results. For example, silica-coated SPIONs can conjugate tumor-based antibodies to enhance the detection and characterization of a lesion, by preferentially pooling in areas of tumor during cell recirculation through therapy and imaging [48]. By further developing two promising functional characteristics (detection via imaging capability or defined therapeutic mechanism), the nanoparticles in question would ultimately serve a key role in theranostic platforms.
Due to their structural stability, biocompatibility, and functional versatility, SPIONs with dual-layered PVA–SiO2 shells can be potentially applied in diverse fields of biomedical applications. Their performance in hyperthermia applications is further improved with shape engineering, with cubic and octopod morphologies outperforming spherical shapes in terms of heating or imaging. In drug delivery, the SiO2 shell acts as a controllable release matrix, and the polymeric role of PVA allows SPIONs to remain stable in aqueous environments. In imaging, functionalized shells can allow SPIONs to target tumor-specific tissues, thus increasing the diagnostic accuracy. Biocompatibility is decentralized between both PVA and SiO₂, which are well-studied materials, and both have the potential for regulatory approval for clinical application [44–48]. Also, it has been reported that Novel PAA-Agarose/Fe3O4@SiO2 nanocomposite exhibit a high negative zeta potential around −30 to −35 mV, indicating strong electrostatic repulsion and enhanced colloidal stability. The hydrodynamic size distribution often shows a narrow polydispersity index (PDI) below 0.2, reflecting uniform particle size and good dispersion in aqueous media. This combination of zeta potential and low PDI confirms that the dual-layer PVA-SiO₂ coating effectively stabilizes the nanoparticles by preventing aggregation and promoting stable aqueous suspension, which is critical for biomedical applications requiring consistent nanoparticle behavior [49].
In summary, SPIONs with dual-layered polymeric–SiO2 shells represent a flexible and ushering platform for contemporary nanomedicine. The dual-layer structure addresses the issue of aggregation and cytotoxicity, while also providing possibilities for functionalizability, targeted delivery, and controlled release of drugs. Furthermore, they are also capable of customizing particle morphology, which is another layer of control that could potentially optimize SPIONs for hyperthermia, MRI, or multi-therapeutic strategies. Ultimately, continued optimization of synthesis methods and functionalization methods will pave the way for enhanced reproducibility and drug-loaded nanoparticles that can be successfully translated for clinical applications in oncology or disease-focused aspects of precision medicine.

Metallic magnetic nanoparticles
Metallic MNPs, such as those composed of cobalt (Co) and nickel (Ni), have garnered significant attention in the biomedical field due to their unique properties and versatile applications. These nanoparticles are particularly valued for their superparamagnetic behavior, which is crucial for applications like magnetic recording media and as contrast agents in medical imaging. The synthesis and functionalization of metallic MNPs are critical to tailoring their properties for specific applications. Techniques such as precipitation, thermal decomposition, and green synthesis methods are employed to control the size, shape, and surface characteristics of these nanoparticles, enhancing their biocompatibility and functionality [18, 30, 44]. In the realm of biomedical applications, metallic MNPs are extensively used as contrast agents in MRI due to their ability to enhance image contrast by altering the local magnetic field, thereby improving the sensitivity and resolution of imaging techniques [29, 45]. Furthermore, the functionalization of MNPs with divalent transition metal coatings, such as Co and Ni, facilitates the immobilization of biomolecules like proteins, enhancing their utility in biosensing and diagnostic applications [26, 46].
The biocompatibility and non-toxic nature of these nanoparticles make them suitable for in vivo applications, including drug delivery systems where they can be directed to specific sites using external magnetic fields, thus minimizing side effects and improving therapeutic outcomes [28, 47]. Additionally, metallic MNPs are employed in hyperthermia therapy, where they generate localized heat to kill cancer cells when subjected to an AMF, showcasing their potential in cancer treatment [28, 44]. Despite their promising applications, challenges such as toxicity, biocompatibility, and nanoparticle aggregation remain, necessitating ongoing research to optimize their design and application in clinical settings [44]. The development of green synthesis methods offers a promising avenue to mitigate some of these challenges by providing eco-friendly and sustainable approaches to nanoparticle production [18]. Overall, the integration of metallic MNPs like cobalt and nickel into biomedical applications continues to evolve, driven by advancements in synthesis techniques and a deeper understanding of their physicochemical properties, which are crucial for their effective application in both diagnostic and therapeutic domains [28, 30, 31, 47, 48, 50, 51].

Synthesis methods
Given their versatility across various applications, significant efforts have been made in recent decades to develop magnetic IONPs. Furthermore, by modifying the reaction conditions, a wide range of nanocrystal forms can be synthesized [34]. The techniques for nanoparticle (NP) fabrication can be categorized into two main approaches: the top-down method, which involves the gradual breakdown of larger systems into nanoscale components, and the bottom-up method, which entails constructing nanomaterials from atomic or molecular precursors. The top-down approach requires meticulous control over environmental factors such as pressure, temperature, and inert atmospheres. However, this method often results in nanomaterials with heterogeneous sizes, shapes, and surface imperfections, which can affect their functionality. In contrast, the bottom-up approach allows for enhanced control over parameters such as size, crystallinity, shape, and reproducibility of the nanomaterials produced. Depending on the specific reaction conditions employed, three primary chemical synthesis techniques for nanoparticles are utilized: solution-based, gas-based, and bio-assisted synthesis methods, as illustrated in (Figs. 1, 2 and Table 2) [52].

Precipitation
The co-precipitation method (Fig. 2a) is indeed a straightforward and chemically efficient approach for synthesizing MNPs, as it allows for the control of various parameters that influence the morphology, size, form, and chemical composition of the nanoparticles. This method involves the mixing of ferrous (Fe-II) and ferric (Fe-III) ions under highly basic conditions, typically using a precipitating agent such as ammonia or sodium hydroxide, to form IONPs [53, 54]. The choice of metallic precursors and the conditions under which they are mixed significantly affect the resulting nanoparticles’ properties. For instance, the pH value during synthesis can influence the morphology and crystal structure, as seen in the synthesis of MnFe2O4 and CoFe2O4 nanoparticles, where higher pH values led to smaller particle diameters and increased agglomeration [55]. Similarly, the use of different precipitating agents, such as NH3 in alcohol or NaOH, can result in variations in magnetic properties and crystallite size, with NH3 in alcohol yielding better magnetic properties but longer response times [56]. The co-precipitation method is versatile and has been employed to synthesize various metal oxide nanoparticles, including manganese ferrite and manganese oxide, which have applications in supercapacitors and as mosquitocidal agents, respectively [57–59]. The synthesis conditions, such as reaction temperature, ageing time, and washing times, also play crucial roles in determining the size and stability of the nanoparticles, as demonstrated in studies on magnetite nanoparticles, where these factors were systematically varied to achieve desired properties [54]. The co-precipitation method for synthesizing MNPs typically yields particles with hydrodynamic diameters in the range of 10–20 nm. The zeta potential of these nanoparticles can be finely tuned from +20 to +40 mV by adjusting the pH and ionic strength of the precipitation medium during synthesis. This control over surface charge helps optimize colloidal stability and dispersion, which is crucial for biomedical applications [60, 61].
Furthermore, surface modifications, such as silica coating, can enhance the functionality of MNPs for specific applications like protein detection, although this may reduce their magnetization saturation [62]. The co-precipitation method’s ability to produce nanoparticles with specific characteristics makes it a valuable technique for creating materials with tailored properties for diverse applications, including magnetic adsorbents for lead removal, where the Langmuir isotherm model was found to best describe the adsorption process [63]. Despite challenges such as agglomeration, which can be mitigated through modifications in the synthesis route, the co-precipitation method’s simplicity, cost-effectiveness, and adaptability to various synthesis conditions make it a preferred choice for producing metal oxide nanoparticles on a large scale [53, 64].
The co-precipitation approach is a straightforward and chemically efficient way to create MNPs [3]. The metallic precursor affects the morphology, size, form, and chemical makeup of nanoparticles. To use this approach, ferrous (Fe-II) and ferric (Fe-III) ions must be mixed under extremely basic circumstances. The production of Fe3O4 with a water-based solution containing ferric salt precursors at ambient temperature in an oxygen-rich environment is explained about the proportion of starting materials, the reaction temperature, the acidity level, and the concentration of ions in the environment (need to be paraphrased). The precipitation of the nanoparticles was caused by the association of the solutions mentioned above without changing the pH and stirring at 50 rpm for 15 min. The mixture that results, known as the black co-precipitate, was separated, cleaned with ethanol and deionized water, and then dried a 50 °C. In their study, analytical-grade chemicals such as CaNO3.4H2O, (NH4)2HPO4, and Fe (NO3)3.9H2O were used without any further treatment to provide a source of calcium, phosphate, and iron, respectively. NaOH and NaF were also used to adjust the pH and prepare the fluoride ion stock solution.
The hydroxyapatite and iron-doped hydroxyapatite with various dopant amounts were synthesized using the co-precipitation technique based on a specific molar ratio. First, separate solutions of phosphate, calcium, and calcium plus iron were prepared, and then the metal source solution was added dropwise to the phosphate source with continuous heating and stirring. The pH was maintained at ten using a sodium hydroxide solution, and the precipitate was washed and dried for characterization and an adsorption study. The synthesized materials were labeled as HA and 1%Fe-HA, 3%Fe-HA, 5%Fe-HA, and 7%Fe-HA for pure and iron-doped hydroxyapatite nanomaterials, respectively. The chemical equations for the synthesis are provided [64].

Hydrothermal method
The hydrothermal approach is widely accepted for generating IONPs using aqueous media. The basic principle is to perform chemical reactions at temperatures above 100 °C, typically under autogenously generated pressures ranging from a few MPa up to ~25 MPa, depending on solvent, precursor concentration, and reactor design [65]. While pressures beyond 25 MPa have been reported in specialized reactors, such conditions are uncommon for routine hydrothermal nanoparticle synthesis [66]. Under such conditions, high crystallinity and monodispersity nanoparticles form with sizes often < 100 nm. Moreover, multiple morphologies would be expected for varying parameters such as precursor type and concentration, precursor-to-solvent ratios, reaction times, and reaction temperatures. In contrast to conventional methods, hydrothermal synthesis provides a means to regulate nucleation and growth to achieve highly crystalline nanostructures. It is worth noting that hydrothermal and solvothermal synthesis are different processes. Hydrothermal specifically states the solvent is water, while solvothermal extends the definition to include organic or non-aqueous solvents (e.g., ethanol, ethylene glycol). The differences in solvent usage have been reported to have considerable impacts on the reaction kinetics and size, shape, and crystallinity of the resulting nanoparticles (Fig. 2a). Both techniques are effective for producing highly crystalline and monodispersed nanoparticles, with the choice of solvent influencing the reaction kinetics, crystal phase, and morphology of the resulting nanoparticles. For instance, a paper by Kuryliszyn-Kudelska et al. discussed the synthesis of Zn/Mn oxide nanoparticles using a microwave-assisted synthesis method [67]. Specifically, zinc nitrate (Zn(NO3)2·6H2O) and manganese nitrate (Mn(NO3)2·4H2O) were dissolved in distilled water; 2 M potassium hydroxide was added to adjust the pH to 11. Once stirred, the solution was transferred to a microwave hydrothermal reactor, and the 3.8 MPa process was completed within 15 min. The resulting nanocrystalline compounds, denoted as (ZnO)1−n(MnO)n (where n ranged from 0.05 to 0.60), demonstrated uniform heat distribution and improved product quality due to microwave assistance [68].

Thermal decomposition method
Thermal decomposition is considered one of the precise methods for producing magnetite particles with limited size distribution and superior crystal quality. In the thermal decomposition process shown in Fig. 2a, iron oxides are (you sometimes use the past tenses, sometimes the present, which should be uniform) created by oxidizing metal precursors in organic solutions. The formation of smaller magnetite or maghemite nanoparticles may also occur depending on the precursor utilized and the presence of other oxidizing agents in the solution. Despite the method’s benefits, such as the ability to produce monodisperse and smaller-sized materials, the produced nanoparticles are only soluble in nonpolar solvents, which precludes their usage in biomedical applications.
An alternate continuous flow manufacturing method for the synthesis of Fe3O4 nanoparticles was developed by Glasgow et al [69]. By mixing the reactants, this process can generate evenly spherical nanoparticles with a high volume. Depending on the kind of precursors used, the thermal decomposition process can produce both metal and metal oxide nanoparticles (NPS). However, massive quantities of hazardous and expensive precursors and surfactants must be used to control the particle size of Fe3O4 NPs when employing the thermal decomposition approach [34]. Building upon prior research, Pekdemir et al. harnessed the thermal decomposition method to synthesize IONPs coated with poly(N-isopropylacrylamide (PNIPA) [70]. Experimental investigations were conducted to create a composite material consisting of Fe3O4@PNIPA nanoparticles, taking into consideration the most favorable conditions. Initially, 0.05 g of Fe3O4 nanoparticles were carefully dispersed in 5 mL of CHCl3 using an ultrasonic homogenizer, allowing them to mix for 1 h. Subsequently, 0.5 g of PNIPA was dissolved in 10 mL of CHCl3, and this solution was added to the previously prepared Fe3O4 mixture, undergoing dispersion for 15 min. Once the dispersion process was complete, the solvent was eliminated using an evaporator, and the resultant PNIPA-Fe3O4 composite was dried in a vacuum oven at a temperature of 40 °C. The thermal decomposition experiments were conducted on the nanocoated PNIPA material using a specialized system controlled by a proportional integral derivative (PID) controller.
The system incorporated a thermally stable, porous, and gas-permeable capsule to hold the sample. The experiments were performed under non-isothermal conditions, with a heating rate of 10 K/min. Inert nitrogen gas circulated within the capsule at a flow rate of 10 mL/min. The system was equipped with sensors to monitor and transfer sensitive scale data to a computer. Thermocouples operating within a PID system with a temperature sensitivity of 0.1 K were utilized. The system allowed for operation under high temperatures (up to a maximum of 973 K), as well as isothermal and non-isothermal conditions [71].

Microemulsion method
A microemulsion (ME) is indeed an isotropic, thermodynamically stable, and transparent dispersion of two immiscible liquid phases, typically oil and water. These systems are stabilized by surfactants and sometimes cosurfactants, forming a flexible interfacial film that separates the microdomains of oil and water (Fig. 2a) [72]. Surfactants lower the tension at the oil-water interface, allowing a single phase to develop. The co-surfactant, which is typically a short-chain amine or alcohol, makes the interface more fluid and also lowers the interfacial tension between the oil and water phases, allowing the oil and water phases to pass through each other more easily [34]. There are three different kinds of ME systems, depending on how the components are arranged: direct (oil dispersed in water, O/W), reverse (water dispersed in oil, W/O), and continuous phase, which contains roughly equal amounts of water and oil [73].
According to reports, this technique allows for more precise control of crystal formation [34]. Due to their ease of preparation (no external energy source is needed) and thermodynamic stability, MEs are efficient drug delivery systems (The separation of ME phases is not readily observed over time, and the majority of MEs exhibit stability for several years) [74]. In addition, Salvador [75] and colleagues documented the synthesis of superparamagnetic magnetite nanoparticles with average sizes ranging from 5.4 to 7.2 nm and significant uniformity through precipitation in a water-in-oil ME. The primary surfactant used was cetyl trimethyl ammonium bromide (CTAB), with 1-butanol as a cosurfactant, and 1-hexanol as the continuous oily phase [75].
In the pursuit of starch superparamagnetic nanocomposites, Moran et al. [71]. opted for the ME method as their synthesis technique. The synthesis of MNPs using the ME technique consists of two main stages. Firstly, ME systems are prepared by mixing an organic phase containing a solvent, alcohol as a co-stabilizer, and a surfactant as a stabilizer with an aqueous phase containing dissolved starch. The surfactant and alcohol molecules arrange themselves into reverse micelles around water droplets in the organic phase. These micelles have hydrophilic heads facing the water droplets and hydrophobic tails facing the organic solvent, resulting in the formation of a water-in-oil (W/O) ME.
The synthesis of NPs using MEs as a medium involves the careful introduction of a precipitating agent, such as a mixture of 12% NaOH and ethanol or pure ethanol, into the ME while maintaining continuous stirring. This process facilitates the formation of small white aggregates, indicative of the formation of silica nanoparticles (SNPs). The ME method is advantageous due to its ability to control the size and shape of the nanoparticles through the self-organization of surfactant phases, which is crucial for achieving uniformity and monodispersed in the final product [76]. Once the SNPs are formed, they undergo multiple washing steps with ethanol and ethanol-water mixtures to effectively remove any excess stabilizers or solvents, ensuring the purity and stability of the nanoparticles. For the synthesis of composite silica nanoparticles-iron oxide nanoparticles (SNPs-IONPs), the process can be adapted to incorporate iron oxide components, potentially using methods that involve surface modification or doping with transition metal oxides, which are known to impart magnetic properties to the nanoparticles [77]. The use of organic solvents in the synthesis process, as highlighted in the production of fluorescent inorganic nanoparticles, can enhance yield and ensure a tighter size distribution, eliminating the need for subsequent size separation [78]. The resulting composite nanoparticles can exhibit unique magnetic and optical properties, making them suitable for a range of applications, including medical and industrial uses, such as in hyperthermal treatments or as components in cosmetic and pharmaceutical formulations [77]. The integration of these methodologies underscores the versatility and potential of ME-based synthesis in producing high-quality, functional nanoparticles [71].

Sol-gel processing
Sol-gel synthesis is considered a practical and affordable process for preparing IONPs (Fig. 2a). The two primary steps of the sol-gel process are the hydrolysis of molecular precursors (such as iron salts (e.g., Fe (NO3)3·9H2O, Fe Cl3) or alkoxides) in basic or acidic media, followed by the polycondensation of the hydrolyzed products [79], both of which are typically completed with a subsequent heat treatment. The sol-gel technique can be precisely controlled by monitoring reaction parameters such as reactant concentration, temperature, hydrolysis rate, and condensation conditions. Compared with other traditional processing methods, this technology offers several advantages, including low reaction temperatures, fine compositional control, and high purity levels.
The sol-gel method has been thoroughly examined and modified to alleviate some of its limitations, such as using organic solvents and the lengthy development process involving multi-step methods. For example, one way to eliminate a polymerization step in the method is to use water-soluble polymers, which also minimizes the environmental impact of using organic solvents [80, 81]. The sol-gel process has been modified for the synthesis of complicated functional materials. For example, Zhang et al. [82]. show a method for preparing neodymium magnets (NdFeB) by employing citric acid and glycol so that these components can form the NdFeB gel, in addition to correct salt formulations of Nd and Fe, and boric acid would yield nanoparticles of ~100 nm [79].
Likewise, CoFe₂/CoFe₂O₄ composites and CoFe₂ alloys were synthesized by Rani and team [83]. utilizing a two-step sol-gel-based method. The first step was to prepare CoFe2O4 nanoparticles via the proteic sol-gel method with Co(NO3)2·6H2O and Fe(NO3)3·9H2O in the presence of flavorless gelatin. The second step was the chemical reduction in a hydrogen (H2) atmosphere at a controlled flow of all three elements of cobalt ferrite. Any reduction temperature of 300 °C for 2 h converted CoFe2O4 particles into CoFe2/CoFe2O4 composites, while treatment at 500 °C for 2 h produced CoFe2 alloys. Next, samples underwent cooling to 25 °C under H2 and were placed in an argon environment to arrest oxidation [84].

Sonochemical method
Sonochemistry involves the use of high-intensity ultrasound to induce chemical reactions and material synthesis (Fig. 2a), primarily through the phenomenon of acoustic cavitation. This process involves the formation, growth, and implosive collapse of bubbles in a liquid, creating extreme conditions such as high temperatures (approximately 5000 K) and pressures (around 1000 bar), with rapid heating and cooling rates exceeding 1010 K/s. These conditions enable unique chemical reactions that are not typically accessible through conventional methods, allowing for the synthesis of a wide variety of unusual materials, including nanostructured materials [85, 86]. In the synthesis of MNPs, sonochemistry has been effectively utilized to produce materials with enhanced properties. For instance, mesoporous iron oxides synthesized sonocchemically exhibit significant magnetic and catalytic properties, with transformations from amorphous Fe2O3 to γ-Fe2O3 upon calcination, enhancing their magnetic behavior [87]. Similarly, γ-Fe2O3 nanoparticles have been coated with octadecyltrihydrosilane (OTHS) using sonochemistry, resulting in increased magnetization due to improved crystallinity and magnetic ordering [88]. The sonochemical synthesis of Fe/Co alloy nanoparticles also demonstrates the method’s efficacy, producing air-stable nanoparticles with high saturation magnetization and soft magnetic properties, attributed to their core-shell structure [89].
Additionally, sonochemistry has been employed to create Janus nanoparticles with magnetic properties, which can stabilize oil-in-water emulsions that are responsive to external magnetic fields [90]. The application of an external magnetic field during sonochemical synthesis can further influence the morphology and magnetic properties of nanoparticles, as seen in the formation of acicular particles and tree-like structures in magnetite nanoparticles, which are otherwise spongelike without the magnetic field [91, 92]. This magnetic field application can also affect the stability and aggregation of nanoparticles, as demonstrated in the synthesis of nickel and cobalt particles, where the field influences their physical properties and colloidal stability [93]. Moreover, the synthesis of iron nitride nanoparticles showcases the versatility of sonochemistry, with different products and magnetic properties achieved under varying conditions, such as the presence of ammonia and hydrogen gases [94]. Overall, sonochemistry provides a powerful and versatile tool for the synthesis of MNPs, offering control over particle size, morphology, and magnetic properties, which are crucial for various applications in catalysis, magnetic storage, and biomedical fields.
For instance, the synthesis of TmVO4/Fe2O3 nanocomposites using a sonochemical method is a notable example of how ultrasound can be employed to enhance the synthesis of nanostructured materials [95]. In the described synthesis process, Fe3O4 nanoparticles are initially dispersed in water and subjected to ultrasound, which aids in the uniform distribution and interaction of particles. The subsequent addition of Tm (NO3)3 and ammonium vanadate solutions under sonication ensures thorough mixing and reaction, leading to the formation of TmVO4/Fe2O3 nanocomposites. The use of ultrasound in this context is consistent with its application in other studies, where it has been shown to enhance the synthesis of MNPs by promoting smaller particle sizes and more uniform morphologies [96, 97]. The calcination step at 550 °C is crucial as it converts Fe3O4 to Fe2O3, a process that has been similarly observed in other studies where thermal treatment is used to achieve desired phase transformations in nanocomposites [98]. The resulting TmVO4/Fe2O3 nanocomposites are expected to exhibit unique properties due to the combination of TmVO4’s optical and catalytic capabilities with the magnetic properties of Fe2O3, which are enhanced by the sonochemical synthesis method [99].
This synthesis approach is not only rapid and cost-effective but also allows for the precise control of the composition and properties of the nanocomposites, making it suitable for various applications, including photocatalysis and environmental remediation [100]. The use of sonochemistry in the synthesis of such nanocomposites highlights its potential in producing advanced materials with tailored properties for specific applications, as demonstrated in the synthesis of other nanocomposites like Fe3O4/MWCNT for electrochemical sensors and Fe3O4/Ag3VO4 for photocatalytic applications [67, 101]. Overall, the integration of sonochemical methods in the synthesis of TmVO4/Fe2O3 nanocomposites exemplifies the innovative approaches being developed to harness the unique properties of nanomaterials for technological advancements.

Biological/green synthesis
The green or biological synthesis of MNPs, particularly IONPs, is a promising approach that leverages natural resources such as plants and microorganisms, including bacteria, fungi, algae, and yeasts (Fig. 2b). This method is advantageous due to its eco-friendliness, cost-effectiveness, and the ability to produce nanoparticles with enhanced properties. Plant extracts are rich in phytochemicals like flavonoids, glycosides, and polyphenols, which serve as reducing, capping, and stabilizing agents during nanoparticle synthesis. These phytochemicals, along with functional groups such as C=C and C=O, play a crucial role in the formation and stabilization of nanoparticles, making them suitable for various in vivo and in vitro applications [102–104].
The green synthesis method is not only environmentally friendly but also produces nanoparticles with superior properties compared to those synthesized by conventional chemical methods. For instance, studies have shown that green-synthesized IONPs exhibit better magnetic and thermal properties, as well as improved stability and biocompatibility, which are essential for applications in medical and environmental fields (Fig. 2c) [103, 105, 106]. The effectiveness of the biological method is further demonstrated in the work of Pathania et al. [107], who synthesized lignin-coated iron oxide nanoparticles (LIONs) using three different approaches: in situ addition, self-assembly using vertexing, and a modified anti-solvent precipitation method with ultrasonication. These methods highlight the versatility and adaptability of green synthesis techniques in producing nanoparticles with specific coatings, which are crucial for their functionality in various applications [107]. The experimental procedures described for synthesizing LIONs and drug-loaded nanoparticles using in situ addition, anti-solvent precipitation, and vortex methods align with various techniques explored in the literature for creating lignin-based nanomaterials.
The in-situ addition method, involving the dropwise addition of lignin to iron oxide and subsequent stirring, is reminiscent of the approach used in the preparation of lignin nanoparticles (LNPs) through nanoprecipitation, which allows for the formation of stable and uniform nanoparticles by controlling the interaction between lignin and solvents [108, 109]. The anti-solvent precipitation method, coupled with ultrasonication, enhances the dispersion and stability of nanoparticles, similar to the techniques used to produce LNPs with distinct morphologies and improved stability across various conditions [109]. This method’s use of sonication parallels the synthesis of lignin-based MNPs adsorbents, which leverage magnetic separation for environmental applications, highlighting the versatility of lignin in forming functional composites with iron oxides [110, 111]. The vortex method, utilizing self-assembly, is akin to the green fabrication approaches for LNPs, where the self-assembly process is crucial for achieving desired nanoparticle characteristics without the need for toxic chemicals [112, 113].
The consistent physical and chemical characteristics of nanoparticles across all methods suggest that the operational parameters, such as concentration, stirring, and sonication, play a critical role in determining the final properties of the nanoparticles, as seen in studies where lignin’s interaction with iron oxides specifically stabilizes certain components like lignin methoxyls, affecting mineralization rates and stability [114]. Moreover, the use of lignin as a biopolymer in these methods underscores its potential in creating sustainable and multifunctional materials, as demonstrated in applications ranging from antimicrobial coatings to drug delivery systems [113]. The lyophilization step ensures the preservation of nanoparticle integrity, a common practice in nanoparticle synthesis to maintain stability and prevent aggregation, which is crucial for their application in diverse fields such as environmental remediation and biomedical sciences [115, 116]. The use of plant-based materials and agro-wastes in green synthesis not only reduces the environmental impact but also utilizes renewable resources, contributing to sustainable development and a circular economy [104, 117]. Moreover, the green synthesis of nanoparticles aligns with the principles of green chemistry, which emphasize the reduction of hazardous substances and energy consumption, further underscoring its importance in advancing sustainable nanotechnology (Fig. 2c) [118, 119].

Application of MNPs in cancer therapy
MNPs have emerged as a promising tool in cancer immunotherapy, offering innovative solutions to overcome the limitations of current treatments. These nanoparticles, particularly magnetite nanoparticles, are being explored for their ability to enhance the efficacy of immunotherapy by modulating immune responses and improving the tumor microenvironment (TME) [113, 120–123]. These nanoparticles can be employed in various strategies, such as MHT, targeted drug delivery, and immune cell modulation. Tanaka et al. [124] demonstrated that magnetite cationic liposomes when subjected to MH, activated dendritic cells (DCs), which led to melanoma regression in mice. This technique leverages localized heating of tumors to not only induce tumor cell death but also trigger immunogenic cell death (ICD), which promotes long-term immune responses. Similarly, Duff and Durum highlighted that fever-range heat treatment enhanced T lymphocyte proliferation, pointing to the role of heat as a trigger for immune activation [125]. Additionally, Wu et al. explored the potential of SPIONs internalized by natural killer (NK) cells, showing that magnetic targeting could improve NK cell infiltration into tumors and inhibit tumor growth. This method highlights the dual role of SPIONs in both guiding immune cells to tumor sites and modulating their activity for enhanced therapeutic outcomes [126].
SPIONs have also been explored as versatile drug carriers for immunotherapy, offering controlled drug release in response to external magnetic fields. Grippin et al. demonstrated that SPION-loaded RNA liposomes achieved a threefold increase in RNA transfection efficiency in DCs when exposed to a magnetic field, enhancing the efficacy of cancer vaccines [127]. Chiang et al. developed multifunctional fucoidan-dextran particles containing SPIONs conjugated with checkpoint inhibitors like anti-PD-L1 and T cell agonizts, which significantly improved survival in tumor-burdened mice by increasing drug accumulation in tumors [128]. Similarly, Brigantine et al. used SPIONs bound to monoclonal antibodies for tumor targeting, achieving notable tumor reduction without immunotoxic reactions. MNPs can be engineered to carry antigens and adjuvants, such as CpG oligonucleotides, to enhance DC activation and CD8+ T cell responses, as demonstrated in a mouse melanoma model, where MNPs covalently modified with antigens induced a potent and sustained immune response [129].
Additionally, MNPs conjugated with antibodies, such as anti-CD3 monoclonal antibodies, have shown potential in reducing T cell-mediated inflammation, highlighting their utility in managing hyperinflammatory conditions. The integration of MNPs with ferroptosis inducers and cell membrane coatings has further enhanced their targeting efficiency and immunogenicity, promoting synergistic effects in tumor ferroptosis and immunotherapy [130]. Moreover, MNPs have been utilized in mild magnetothermal therapy to activate both innate and adaptive immunity, facilitating immune cell infiltration into solid tumors and overcoming the immunosuppressive barriers of the TME [131]. Their unique properties, such as magnetic responsiveness and biocompatibility, allow MNPs to be used in theranostic applications, combining diagnostic imaging with therapeutic interventions, including MHT and drug delivery [132]. The ability of MNPs to manipulate the immune system in vivo, enhance tumor accumulation of immunotherapeutic agents, and create an immunotherapy-sensitive environment underscores their potential in boosting cancer immunotherapy [133]. These studies highlight how MNPs can improve the spatial precision of drug delivery, enhance immune cell activation, and increase the efficacy of immunotherapies by combining the properties of magnetic targeting with controlled release mechanisms, thus overcoming many of the challenges in traditional cancer treatments like chemotherapy or radiotherapy.

Evaluation of MNPs in anti-tumor applications (in vitro study)
The following evaluation provides a comparison of the anti-tumor efficacy of different types of MNPs based on their composition and surface functionalization. These nanoparticles are widely studied for their potential in cancer treatment, particularly for targeted drug delivery, MHT, and imaging applications.

Oxide MNPs
IONPs, particularly magnetite (Fe3O4) and maghemite (γ-Fe2O3), have garnered significant attention in the field of cancer therapy due to their unique magnetic properties, biocompatibility, and ease of synthesis. These nanoparticles are primarily utilized in MHT, where they generate localized heat in the presence of an AMF, effectively inducing hyperthermia to kill cancer cells. This mechanism of action is well-documented, with temperatures of 41–46 °C being sufficient to inhibit tumor growth, induce apoptosis, or kill tumor cells directly [134, 135]. When exposed to an AMF, the magnetic domains within the NPs align and realign rapidly. This rapid alignment and realignment process is known as magnetic hysteresis. During hysteresis, energy is dissipated in the form of heat due to the friction between the magnetic domains as they rotate and rearrange. The generated heat can cause a significant increase in temperature within the local environment of the NPs. This temperature rise can be substantial, reaching levels that are cytotoxic to cancer cells. This heat generation can cause a significant temperature to increase in the local environment of the NPs, leading to damage to cancer cells through mechanisms such as protein denaturation, DNA damage, and membrane damage [136]. Factors affecting hyperthermia include NP size and shape, magnetic field strength and frequency, NP concentration, and NP dispersion [137, 138]. The advantages of hyperthermia include selective targeting, minimal damage to healthy tissue, and synergistic effects with other cancer treatments. By understanding these factors and mechanisms, researchers can optimize the design and application of iron oxide NPs for effective cancer therapy [136].
The superparamagnetic nature of these nanoparticles allows their magnetization to be switched on by an external magnetic field, making them highly effective in localized cancer treatments [139, 140]. In vitro studies have demonstrated the efficacy of IONPs in various cancer cell lines, including pancreatic carcinoma, uveal melanoma, breast adenocarcinoma, triple-negative breast cancer, lung cancer, and colon cancer, where they have shown concentration-dependent cytotoxicity and enhanced cellular uptake [141]. Furthermore, IONPs can be functionalized to carry chemotherapeutic drugs and tumor suppressor microRNAs, enhancing their anti-tumor efficacy when combined with MHT [141]. The biocompatibility and biodegradability of IONPs make them suitable for biomedical applications, including drug delivery systems that utilize external magnetic fields to target cancer cells while minimizing damage to healthy tissues [142, 143].
Additionally, IONPs can generate reactive oxygen species (ROS) and induce ferroptosis, a form of programmed cell death, further contributing to their cytotoxic effects on cancer cells [142]. The combination of MHT with other therapies, such as photothermal therapy (PTT) and PDT, has shown synergistic effects, enhancing the overall therapeutic outcomes in cancer treatment [144]. The potential of IONPs in cancer therapy is further supported by their ability to serve as drug carriers, allowing for spatially, temporally, and dosage-tunable drug release with minimal side effects [143]. SPIONs have been extensively studied for their drug-loading efficiency, cytotoxic potential, and diagnostic abilities, making them promising candidates for combinatorial therapeutic purposes [145]. The synthesis and functionalization of these nanoparticles are crucial for optimizing their magnetic characteristics and ensuring stable composition and physical parameters, which are essential for their application in targeted drug delivery and MHT [146]. Wang et. al. have developed M2 macrophage-targeted IONPs for magnetic resonance image-guided MHT therapy in cancer treatment [123]. The primary goal is to selectively target and eliminate M2 tumor-associated macrophages (TAMs) to inhibit tumor progression and remodel the tumor immune microenvironment (TIME).
Also, the researchers developed SPIONs functionalized with an M2 macrophage-targeted peptide (M2pep). These nanoparticles effectively target M2 macrophages and induce localized heating to destroy tumor cells when exposed to an AMF. The SPIO-M2pep nanoparticles demonstrated significant efficacy in both in vitro and in vivo models. In vitro, they efficiently targeted M2 macrophages and induced cell death under AMFs. In vivo, the nanoparticles significantly reduced tumor volume, decreased the population of pro-tumoral M2 TAMs, and remodeled the TIME by promoting anti-tumor immune responses (Fig. 3).
Furthermore, the nanoparticles exhibited good biocompatibility and high targeting efficiency, making them promising candidates for MR imaging-assisted MHT therapy. The study concludes that the SPIO-M2pep nanoparticles hold significant potential for improving cancer therapy outcomes by effectively targeting M2 TAMs, enhancing MRI capabilities, and remodeling the TIME. This approach could lead to more effective and targeted cancer treatments with reduced side effects. Despite the promising results, the exact mechanism of cell death induced by N, whether due to heating or nanoparticle toxicity, remains to be fully elucidated, highlighting the need for further research to optimize their application in cancer therapy [147]. Overall, the in vitro studies underscore the potential of IONPs as effective anti-tumor agents, paving the way for their development in clinical settings [148].

Metal magnetic nanoparticles (MNPs)
Metal-based MNPs, particularly those containing Iron (Fe), Cobalt (Co), and Nickel (Ni), are emerging as potent tools in cancer therapy due to their strong magnetic properties and capacity for MHT. These nanoparticles generate heat under an AMF, enabling targeted cancer cell destruction through hyperthermia. As they are exposed to AMFs, MNPs convert electromagnetic energy into heat via magnetic hysteresis loss. This heating effect is especially useful for achieving cytotoxic temperatures (41–46 °C), which can selectively damage cancer cells by inducing protein denaturation, DNA damage, and membrane disruption while sparing surrounding healthy tissue [149, 150].
Iron-based MNPs, especially magnetite (Fe3O4), exhibit high magnetic saturation and strong heat-generating abilities when exposed to AMFs, making them effective in cancer hyperthermia. Studies have shown that Fe-based nanoparticles can induce cell death in cancer types such as breast cancer and prostate carcinoma, both in vitro and in vivo. Additionally, Fe-based MNPs can be functionalized with biocompatible coatings like chitosan or carboxymethylcellulose, enhancing stability and drug delivery capacity. This allows for combined hyperthermia and chemotherapy treatments that leverage the nanoparticles’ dual therapeutic effects [151, 152].
Cobalt-based MNPs are known for high magnetic anisotropy and thermal stability, making them well-suited for high-frequency AMF applications. When combined with iron in FeCo alloys, their magnetic properties, such as coercivity and saturation magnetization, are enhanced, increasing heat generation efficiency in hyperthermic treatments. For example, FeCo nanoparticles coated with polyaniline (PANI) reduce cytotoxicity and improve dispersion, which enhances their therapeutic usability. However, due to the cytotoxicity of cobalt ions, these MNPs often require additional biocompatible coatings or hybrid structures to ensure safety in medical applications [153, 154].
Nickel-based MNPs, though less commonly used due to potential cytotoxic effects, have shown promising results in controlled hyperthermia. Ni-based particles produce efficient heating and are often synthesized in core-shell structures to minimize nickel ion release, enhancing biocompatibility. Studies using Ni-coated iron nanoparticles report effective magnetic responsiveness with reduced toxicity, indicating potential for Ni-MNPs in cancer therapies requiring precise thermal control and localized treatment (Fig. 4) [155, 156]. As shown in Fig. 4a, in a study by García-Soriano et al. Iron oxide multicore nanoparticles were synthesized using a two-step seeded-growth procedure. Initially, IONPs with average sizes of 7 and 11 nm, spherical shapes, and narrow size distributions were created through thermal decomposition in 1-octadecene. In the second step, these IONPs were used as seeds, and iron(III) acetylacetonate ([Fe(acac)3]) was thermally decomposed in oleic acid to form multicore structures. The seed concentration was adjusted to maintain a consistent surface area for growth, resulting in nanoclusters. The 7 nm seeds formed flower-like clusters (56 nm) resembling iron oxide nanoflowers, while the 11 nm seeds produced 23 nm anisotropic nanoclusters, appearing as irregular polygons. The hydrophobic products were then converted to an aqueous dispersion using meso-2,3-dimercaptosuccinic acid (DMSA) for biological applications[155.
Also, Fig. 4b shows that XPS and XRD analyses confirmed the Fe3+ maghemite phase in the nanoparticles. Crystallite sizes were 8.9 nm for 56 nm nanoflowers and 11.9 nm for 23 nm nanopolygons, as verified by TEM. Magnetic measurements showed saturation magnetization (MSM_SMS) values of 70 A m222/kg for NC23 and 64 A m2 22/kg for NC56, with ferrimagnetic behavior and low coercive fields. DMSA-coated NC23 and NC56 formed stable dispersions in water, with hydrodynamic diameters (43 nm and 90 nm, respectively) increasing slightly in cell culture media due to protein adherence. SAR values under an AMF were 1540 W/g for NC23 and 305 W/g for NC56, influenced by core sizes (12 nm for NC23, 9 nm for NC56) and magnetic coupling. Despite synthesis-related boundaries, the SAR values are comparable to polyol-synthesized nanoflowers, demonstrating excellent heating efficiency [155]. In viability assays, PANC1 (pancreatic carcinoma), Mel202 (uveal melanoma), and MCF7 (breast adenocarcinoma) cell lines were treated with NC23 and NC56 nanoparticles at varying concentrations for 24 h, and cell viability was assessed 72 h post-treatment. The toxicity levels differed significantly among cell lines and nanoparticles, indicating cell-specific responses. While factors like radical oxygen species (ROS) production do not fully explain this variability, differences in cell surface molecules (proteins, sugars, and phospholipids) may influence nanoparticle-cell interactions and toxicity levels. Notably, NC56 showed significant toxicity across all cell lines at concentrations above 0.05 mg/mL of iron (Fig. 4c) [155].
Figure 4d shows that for NC23, significant toxicity was observed at concentrations above 0.075 mg/mL in PANC1 and Mel202 cells and above 0.15 mg/mL in MCF7 cells. Based on these findings, 0.05 mg/mL was chosen for further characterization. To induce cell death through magnetic heating, nanoparticle-cell association or internalization is crucial. TEM imaging after 24-h incubation showed that NC23 and NC56 retained their original shapes, including the distinct flower-like morphology of NC56. Nanoparticles were found near cell membranes (suggesting endocytosis) and accumulated predominantly in the cytoplasm, often within endosomal compartments containing 3–25 nanoparticles or more per vesicle [155]. The uptake of iron by cells was measured using a colorimetric ferrozine assay at various incubation times (2, 4, 8, 24, 48, and 72 h). For both nanoparticle types and all three cell lines, the detected iron concentration steadily increased over time, indicating continuous nanoparticle internalization by the cells throughout the 72 h (Fig. 4e).
The activity of various nanostructures was tested across multiple cancer cell lines, including pancreatic, breast, colon, lung, and uveal melanoma, both with and without an AMF. Results showed cell-line-dependent efficacy, with MCF7 being the most resistant, exhibiting reduced viability only under AMF application. The NC23-miRmix sample alone showed minimal impact on cell viability, except in A549 cells, where AMF slightly enhanced its effect. Formulations containing SN38 demonstrated activity with or without AMF, underscoring the potential of combining chemotherapy with MHT for enhanced antitumor effects (Fig. 4f). Prior studies highlighted improved outcomes using similar approaches. For example, IONPs functionalized with chemotherapeutics like 5-FU, combined with AMF, significantly reduced tumor volumes and increased cell death in glioblastoma, colorectal cancer, and bladder cancer models. Notably, doxorubicin (DOX)-loaded IONPs showed better efficacy when combined with hyperthermia, achieving up to 94% reduction in MCF-7 viability with high doses and immediate AMF application [157–159].
To mitigate cytotoxicity and improve therapeutic efficiency, metal MNPs are often encapsulated in biocompatible coatings or formed in core-shell configurations. These functional modifications not only reduce toxicity but also improve nanoparticle stability and allow for drug conjugation. Coatings such as PANI or chitosan are used to encapsulate FeCo nanoparticles, enabling safe MHT while serving as drug carriers for targeted chemotherapy, which helps in reducing systemic side effects [154, 156]. In vitro studies have demonstrated that metal MNPs display high magnetic responsiveness and concentration-dependent cytotoxicity across various cancer cell lines, effectively inducing hyperthermia. The ability to tailor the magnetic and thermal properties of these MNPs through functionalization has led to their integration in multimodal cancer therapies. For instance, drug-loaded nanoparticles like methotrexate-coated FeCo MNPs have shown synergistic effects in cancer cell apoptosis when combining hyperthermia and chemotherapy, highlighting their potential for targeted cancer treatment with enhanced therapeutic efficacy [156, 160].
In a recent study by Sonia Iranpour et al., researchers developed an advanced drug delivery system using magnetic mesoporous SNPs (SPION@MSNs) for targeted colorectal cancer therapy. This system integrates a superparamagnetic iron oxide core to enable imaging and magnetic responsiveness with mesoporous silica for drug loading and controlled release. The SPION@MSNs were modified with gold nanoparticles as pH-sensitive gatekeepers, which enabled selective release of the chemotherapeutic agent DOX in the acidic TME. Furthermore, PEGylation enhanced the biocompatibility of the nanoparticles, and an EpCAM aptamer was conjugated for targeted delivery to colorectal cancer cells. As a result, the targeted SPION@MSNs demonstrated significant accumulation in tumor tissues, improved DOX release at acidic pH, and high specificity for EpCAM-positive cancer cells, reducing off-target effects. Both in vitro and in vivo studies confirmed that the targeted system effectively suppressed tumor growth and minimized toxicity compared to free DOX and non-targeted systems, highlighting the potential of SPION@MSNs in enhancing therapeutic outcomes while reducing side effects in cancer treatment. For instance, they reported that the targeted nanocarrier (Apt-PEG-Au-NPs@DOX) had a significantly lower IC₅₀ (e.g., 9.72 µg/mL at 24 h) in EpCAM-positive HT-29 cancer cells compared to the non-targeted version, indicating higher potency. In contrast, its IC₅₀ was much higher in EpCAM-negative CHO cells, demonstrating selective targeting and reduced off-target toxicity. Overall, metal-based MNPs such as Fe, Co, and Ni exhibit unique magnetic and thermal properties, making them versatile candidates for applications in cancer hyperthermia, targeted drug delivery, and multimodal therapy [161].

Shell-functionalized oxide magnetic nanoparticles (MNPs)

Biocompatibility and functionalization
Surface coating of oxide MNPs is critical to improving biocompatibility, stability, and minimizing cytotoxicity for biosystems in biomedical applications for drug delivery, hyperthermia treatments, etc. Functionalization allows MNPs to maintain magnetic properties, improve dispersion in biological systems, and improve the therapeutic action [162, 163]. Coatings (i.e., polydopamine, silica, and polyethylene glycol (PEG), provide improved colloidal stability under physiological conditions and attenuate aggregation. For instance, PEG-coated IONPs capable of remaining stable in the bloodstream increased circulation time and reduced immunogenicity and clearance, aiding in targeting the tumor [162–164]. Polydopamine-coated nanoparticles provide not only stabilization of your nanoparticles but also have drug conjugation capabilities, leading to the development of a multifunctional platform for drug delivery and hyperthermia [165]. Studies both in vitro and in vivo have shown the efficacy of coatings in cellular uptake, increase in therapeutic index, and maintenance of key magnetic properties required for hyperthermia application, dependent on drug release agents [126, 162, 163, 166, 167].

Controlled drug release and hyperthermia
Surface functionalized MNPs can also be designed for controlled drug release and to improve/increase MHT. For example, mesoporous silica-coated SPIONs can be loaded with chemotherapy anticancer drugs and can be further modified to have a stimuli-responsive polymer layer that will allow localized releases of drugs in neutral or acidic conditions used in the targeted TME [162, 163, 167]. This would allow the avoidance of systemic effects on health without loss of overall health if using nondrug delivery options, alleviating several health implications while improving therapeutic outcomes.
With thermal [127, 166, 168] or hyperthermia, polydopamine-coated SPIONs are specifically chosen to study the alterations in their heating efficiency when using an AMF, when the amount and type of SPIONs are known, which allows for focused localized application, with whole tumor cell death observed with the incorporated drug [127, 166, 168]. Similarly, Sheervalilou et al [165]. studied another approach to glioma therapy, looking at the incorporation of high magnetic saturation graphene oxide using magnetic graphene oxide nanoheaters (GOMNPs). The GOMNPs were ~34 nm with a low −35 mV surface charge and were deemed stable, low toxicity, and high SAR. Under AMF, they generated both hyperthermia and ROS, inducing apoptosis in glioma-bearing rats and significantly extending survival.

Immunomodulation and the abscopal effect
Surface-modified MNPs can combine hyperthermia with immunotherapy. A multifaceted platform for cancer immunotherapy based on engineered magnetic nanostructures has been comprehensively investigated by researchers, highlighting the unique properties of MNPs to enhance immunotherapy effectiveness. These magnetic nanostructures can serve as carriers for immunotherapeutic agents, facilitate targeted delivery via magnetic guidance, and enable localized hyperthermia for tumor ablation, thus combining multiple therapeutic mechanisms (Fig. 5) [169]. These platforms showcase how their physical design and biological functionalization can be harnessed to combat cancer. The core magnetic nanostructures are fabricated in various morphologies—including nanospheres, nanoplates, nanocubes, and Janus or core-shell configurations—which are then coated with biocompatible layers like polymers or phospholipids to ensure stability. These coated nanostructures are subsequently loaded with a diverse array of immunotherapeutic agents, such as the viral mimic poly(I: C), antibodies, tumor-associated antigens (TAAs), and even NK cells, to create an integrated system that actively directs and stimulates the immune system to target and destroy tumor cells.
For example, MNPs with immunostimulants, such as R837 hydrochloride, can stimulate some immune responses while delivering magnetic heating and triggering TAA release and immune cell recruitment [157–159, 164, 170]. Beyond local tumor control, CoFe2O4@MnFe2O4 nanoparticles showed improved immune activation via scope. The hard–soft magnetic interface enhanced hyperthermia efficiency while inducing DC maturation and activating CD8+ T-cells. In combination with AMF, anti-PD-L1 was effective in mice and produced systemic antitumor effects, even including secondary tumor elimination (abscopal effect) [170].

Phototherapeutic synergies
Functionalized oxide MNPs can also interact with light-based therapies and even create synergistic therapy. Methylene blue–immobilized copper–iron nanoparticles (MB-CuFe NPs) showed phototherapeutic effects in HeLa cells. Those nanoparticles acted as Fenton catalysts, generating ROS and keeping their superparamagnetic properties favorable for MRI [166, 170]. The methylene blue photosensitizer also enhanced PDT under 660 nm light, generating singlet oxygen, thereby maximizing cancer cell killing. These multifunctional NPs show the advancement of PDT, magnetic, and imaging functions on a single platform.

Targeting cancer stem cells (CSCs)
Cancer stem cells (CSCs) present a unique therapeutic challenge for cancer therapy because they tend to be resistant to most chemotherapeutic agents [171]. For instance, cobalt ferrite nanoparticles with citric acid and PEG coatings were used to target CSCs through combined MHT, PTT, and PDT therapy. The multifunctional nanoparticles generated hydroxyl radicals and heat and were reported to decrease CSC numbers within both melanoma (A375) and breast cancer (MDA-MB-231) cancer cell lines. The decrease in CD133⁺/CD44⁺ CSCs was confirmed by flow cytometry and was substantially greater under MHT + PTT + PDT directional therapies [172].
In a study by Liya Wu [126], the delivery of Fe₃O₄@PDA nanoparticle-labeled NK cells to A549 cancer cells was investigated, and NK cells were cocultured with or without Fe3O4@PDA nanoparticles (NPs) at concentrations of 50 μg/mL or 100 μg/mL for 72 h. Afterwards, the cells were stained with anti-CD, anti-CD56, and anti-CD69 antibodies for immunophenotypic analysis via flow cytometry. Also, they examined Fe₃O₄@PDA nanoparticle (NP)-labeled NK cells targeting A549 lung cancer cells using magnetic traction. The NPs, averaging 50–60 nm, showed stable size and uniform PDA coating, which enhanced cellular uptake. NK cells cocultured with 50 or 100 μg/mL NPs for 72 h showed no changes in surface markers, cell cycle, apoptosis rates, or cytokine secretion (IFN-γ, TNF-α), indicating NP biocompatibility and no induced maturation. Also, they found that magnetic devices under culture plates enriched NP-labeled NK cells at tumor sites, moderately increasing cytotoxicity against A549 cells at effector-to-target ratios of 10:1–20:1. In vivo, using BALB/c nude mice with implanted magnets, NP-NK+ magnetic field (M) treatment significantly suppressed tumor growth compared to controls.
As mentioned above, CSCs drive tumor growth and recurrence by resisting conventional therapies [173]. A new tool for combating them is microrobots. Microrobots offer a promising solution by enabling a multi-pronged attack [174]. They can be magnetically guided to the tumor site to deliver high drug doses directly to CSCs, disrupt their protective niche, and even physically ablate them via hyperthermia [175]. Furthermore, they can be engineered for localized immunotherapy, reprogramming the immune system to specifically target CSCs [176]. Microrobots represent a cutting-edge approach in biomedicine, leveraging microscopic, controllable agents for targeted therapeutic delivery [177].
For instance, Nguyen et al. [178] this study develops NK-Robots, a cell-based microrobot for cancer immunotherapy, by conjugating NK cells with MNPs via a pH-sensitive polymer linker. This design enables magnetic guidance to tumors and acidic-triggered MNP release in the TME. The system provides a dual attack: the NK cells directly kill cancer cells, while the liberated MNPs repolarize TAMs from a pro-tumor (M2) to an anti-tumor (M1) state. In vivo results demonstrated that these microrobots significantly enhanced tumor targeting and suppressed tumor growth, offering a promising, drug-free platform for effective cancer treatment.
The innovative NK-Robot platform (Fig. 6a) was fabricated by covalently tethering MNPs coated with a pH-sensitive maleimide-functionalized polymer (mal-PC) onto NK cells, enabling magnetic guidance and acidic-tumor-environment-triggered release. The system provides a dual attack: the NK cells directly kill cancer cells, while the liberated MNPs repolarize TAMs from a pro-tumor (M2) to an anti-tumor (M1) state (Fig. 6b, c). Their results revealed that mal-PC@MNPs significantly decreased secretion of the M2 cytokine IL-10 (Fig. 6d) and increased secretion of the M1 cytokines TNF-α and IL-6 (Fig. 6e, f). The in vivo efficacy of this system showed that magnetic guidance drastically enhanced NK-Robot accumulation at the tumor site (Fig. 6g) and resulted in the most potent tumor growth inhibition over 28 days compared to all other treatment groups, including NK cells alone (Fig. 6h–j), validating the success of this dual-targeted, dual-therapeutic strategy.
In vitro studies provide compelling evidence that shell-functionalized metal nanoparticles enhance the efficacy and safety of MHT and drug delivery systems. Functional coatings reduce cytotoxicity and improve the biodistribution of the nanoparticles, which are critical for their future clinical applications in cancer therapies. Through precise control over targeting and release, these nanoparticles hold significant promise as a key component in the next generation of cancer treatments, particularly when integrated with immunotherapy and magnetic-based approaches [179, 180].

Shell-functionalized metal magnetic nanoparticles (MNPs)

Biocompatibility and functionalization
Surface functionalization of metallic cores using polymers or silica is helpful for circumventing toxicity. Coatings prevent oxidation, reduce metal ion leaching, and stabilize nanoparticles in biological environments. Functionalization decreases aggregation, increases biodistribution, and enhances therapeutic index while retaining magnetic properties.

Controlled drug release and hyperthermia
Functionalized metallic MNPs can be designed to release drugs magnetically. Lu et al. [181]. demonstrated this with gold-coated cobalt nanoparticles encased in polyelectrolyte microcapsules realized by layer-by-layer self-assembly. Under an AMF (100–300 Hz, 1200 Oe), the walls of the microcapsules distorted to a disordered state that assimilated larger-sized macromolecules like FITC-dextran. This proof-of-concept suggested that ferrogels may be useful for on-demand, controlled drug delivery.

Immune modulation and the abscopal effect
Pan et al. [163] created CoFe2O4@MnFe2O4 NPs containing a magnetically hard cobalt ferrite core and a soft manganese ferrite shell. These design changes contributed to the efficacy of hyperthermia energy absorption. They demonstrated enhanced DC activation and cytotoxic T-cell response in vivo. When paired with AMF and anti-PD-L1, they showed the abscopal effect and eliminated distant (secondary) tumors. The toxicity of cobalt remains a barrier to its clinical potential.

Phototherapeutic Synergies
Kuo et al. [170] synthesized methylene blue–immobilized copper-iron–iron nanoparticles (MB-CuFe NPs) in one step by a hydrothermal method. The nanoparticles were ROS-generating Fenton catalysts while also functioning as the PDT agent under 660 nm irradiation. MTT assay revealed low cytotoxicity, and biodegradation in acidic environments supported tumor test delivery for cancer therapy. They also demonstrated superparamagnetic, suggesting this may support MRI applicability making them multifunctional.

Targeting cancer stem cells (CSCs)
Citric acid and PEG-coated cobalt ferrite nanoparticles were specifically engineered to target CSCs. In combination with PTT, PDT, and MHT, it contributed significantly to CSC populations in melanoma and breast cancer models [166]. The combination treatment induced a synergistic eradication of the CSC population in the treatment groups, resulting in a more effective treatment compared to using just one modality.

Summary
In vitro and in vivo studies often suggest that shell-functionalized oxide and metallic MNPs improve efficacy and safety within hyperthermia and drug delivery therapies. The function of nanoparticles, specifically related to the reduction in toxicity and improvement in biodistribution, in multifunctional therapies involving synergism with immunotherapy, phototherapy, etc., is a unique path forward in cancer therapy using MNPs [82, 168].
To mitigate the potential toxicity associated with metal MNPs, functionalization with coatings such as polymers and silica is essential. These coatings not only shield the core metal particles from oxidation but also reduce the release of potentially toxic metal ions, making these nanoparticles safer for biomedical applications [160]. Enhanced Biocompatibility and Targeting: Coatings on metal MNPs improve biocompatibility, allowing these nanoparticles to retain their superior magnetic properties while enhancing their stability and dispersibility in biological environments. Functionalization also reduces aggregation, thereby improving targeting efficacy and the therapeutic index of the MNPs. In vitro studies have demonstrated that shell-functionalized metal nanoparticles exhibit significantly enhanced anti-tumor effects, especially when applied to MHT and targeted drug delivery systems. These coatings are crucial in reducing cytotoxicity while maintaining the magnetic properties essential for targeted therapeutic applications [161]. Controlled Drug Delivery and MHT: Research shows that functionalized metal MNPs can be engineered for magnetically triggered, controlled drug release. Lu et al. demonstrated this potential by using gold-coated cobalt nanoparticles embedded within polyelectrolyte microcapsules. These capsules were fabricated through a layer-by-layer self-assembly process and incorporated cobalt-gold nanoparticles with a 3 nm diameter [181]. When exposed to AMFs at frequencies between 100-300 Hz and a magnetic induction of 1200 Oe, the Co@Au nanoparticles caused the capsule walls to distort, enhancing permeability to macromolecules such as FITC-labeled dextran. This study underscores the potential of these ferrogels for controlled, on-demand drug delivery by carefully adjusting the composition, structure, and parameters of applied AMFs. Moreover, a summary of in vitro studies has been presented in Table 3.
Improving energy efficiency in cancer therapies: Pan et al. addressed the relatively low energy efficiency of MHT compared to photon-based systems like PTT by developing CoFe2O4@MnFe2O4 nanoparticles, which feature a magnetically hard cobalt iron oxide core and a magnetically soft manganese iron oxide shell [163]. The interface between these hard and soft magnetic materials resulted in improved hyperthermia performance. Additionally, these nanoparticles promoted DC maturation and cytotoxic T-cell activation, generating TAAs in mouse models. In combination with AMF and anti-PDL1 treatment, the particles triggered a series of immune responses involving DCs, CD8+ T cells, and pro-inflammatory cytokines, effectively enabling secondary tumor elimination and demonstrating the abscopal effect. However, the cobalt core’s potential toxicity poses challenges for clinical translation.
Advances in Phototherapeutic Applications: In an investigation by Kuo et al., methylene blue-immobilized copper-iron nanoparticles (MB-CuFe NPs) exhibited enhanced phototherapeutic effects on HeLa cells. These nanoparticles, synthesized via a one-step hydrothermal method, allowed for a customizable Fe/Cu ratio, with a metal concentration of 25 ppm proving most effective at reducing cell viability [170]. Functioning as Fenton catalysts, MB-CuFe NPs generated ROS from hydrogen peroxide, showing strong fluorescence signals indicative of ROS production. Furthermore, their superparamagnetic properties suggested potential MRI applicability. The FDA-approved photosensitizer methylene blue enabled drug delivery into cells, enhancing PDT at 660 nm by producing singlet oxygen species and thus increasing cancer cell damage. MTT assays confirmed low cytotoxicity, and the nanoparticles showed biodegradability in acidic environments, highlighting their potential in combined PDT and thermal cancer therapies.
Targeting cancer stem cells (CSCs): CSCs present a challenge in cancer therapy due to their resilience to conventional treatments. A novel approach developed cobalt ferrite nanoparticles coated with citric acid and PEG, targeting CSCs [166]. These nanoparticles were highly effective in generating hydroxyl radicals and heat during MHT. When combined with PTT and PDT, the treatment synergistically reduced CSC populations in A375 and MAD-MB-231 cell lines. Flow cytometry revealed that the combined MHT + PDT + PTT treatment more effectively decreased the CD133 + CD44 + CSC population in A375 cells compared to MAD-MB-231 cells, underscoring the nanoparticles’ potential to enhance treatment outcomes by eradicating CSCs through a multifunctional therapeutic approach (Fig. 7) [182, 183].
In summary, in vitro studies consistently support that shell-functionalized metal nanoparticles enhance both the efficacy and safety of MHT and drug delivery systems. By reducing cytotoxicity and improving biodistribution, these functional coatings enable the integration of MNPs with additional therapeutic modalities like immunotherapy and phototherapy, paving the way for advanced cancer treatment solutions [82, 168].

In vivo application of metal nanoparticles
The anticancer effect of the metal NPs in animal models has been examined in several studies. Compared to tumor controls, silver NPs helped to extend the survival time in the tumor mouse model (over 50%) [184]. In addition, silver nanoparticles can reduce the amount of ascites fluid (65%), so tumor-bearing mice regain their normal body weight. On a mouse model, bis(2,4-pentanedionato) copper (II) encapsulated chitosan NPs were examined, with the control group having a tumor volume of 1200 mm3. The non-targeted and targeted NPs were given at a dose of 2000 μg/kg, which decreased the tumor volume (600 mm3 and 125 mm3, respectively [50].
However, more in vivo research findings are required for an in-depth comprehension of the mechanisms and modes of nanoparticle clearance (Table 4). This knowledge is essential for the creation and advancement of innovative anti-cancer medications in the field of nanomedicine [51].

Evaluation of MNPs in anti-tumor applications (in vivo study)

Iron oxide nanoparticles
IONP are considered inorganic metal oxides. The therapeutic use of IONPs has been approved for diseases such as cancer [185, 186]. It has many outstanding properties, such as stability, safety, and biocompatibility, as well as enhancement of drug delivery and combination therapy effects [187]. The application of IONPs in cancer treatment has been approved in many in vivo studies [188, 189].
For instance, in an interesting study, Zhou, et al. [190], Zhou et al. developed a bovine serum albumin-coated (IONPs@BSA) nanocarrier loaded with the anticancer drug mitoxantrone (MTX). They evaluated its antitumor effects in 4T1 breast tumor-bearing BALB/C mice. Treatment with IONPs@BSA–MTX increased DC (CD11c + CD86+) maturation in lymph nodes and activated T cells (CD3 + CD4+ and CD3 + CD8+) in the spleen compared to free MTX, indicating enhanced immune response. The IONPs@BSA–MTX group showed the smallest tumor volume and improved survival without body weight changes. Also, MRI analysis confirmed effective delivery of IONPs@BSA to the tumor, as evidenced by gradual tumor darkening over 24 h and reduced MR signal 3 h post-injection. Additionally, MR imaging of lymph nodes revealed darkening after IONPs@BSA injection, indicating particle accumulation. Enlarged MR images of lymph nodes taken 2.5 h post-injection showed intensified darkening compared to pre-injection images, suggesting potential for monitoring tumor metastasis. These results demonstrate that IONPs@BSA–MTX enhances antitumor immunity, effectively targets tumors, and allows noninvasive tracking of nanoparticle delivery and lymph node involvement in breast cancer treatment.
Also, in another study by Huang et al. [191], develops MNPs (Fe₃O₄@Ca/MnCO₃) to enhance DC cancer vaccines. Under a magnetic field, the nanoparticles efficiently deliver tumor antigens into the cytoplasm of DCs. Their degradation releases Mn2+ and Ca2+, which activate the STING pathway and increase autophagy, promoting antigen cross-presentation. This leads to stronger DC maturation, increased CD8⁺ T cell proliferation, improved lymph node migration, and higher antibody levels. The strategy offers a novel, effective, and safe approach to improve the cellular immune response of DC-based vaccines. They characterized these developed multifunctional Fe3O4@Ca/MnCO3 MNPs, by TEM and SEM (Fig. 8a–c), which showed a flower-like morphology and demonstrated significantly superior antigen-loading capacity (56 µg/mg) compared to uncoated Fe3O4 nanoparticles (Fig. 8d). This enhanced delivery system, when applied under a magnetic field, actively promoted antigen internalization by DCs, leading to their potent activation. Consequently, these activated DCs demonstrated a remarkable ability to stimulate CD8⁺ T cell proliferation in vitro (Fig. 8e). Furthermore, the DC vaccines exhibited enhanced migration to lymph nodes in vivo, as evidenced by both a stronger fluorescent signal from the delivered antigen and a visible increase in lymph node size and cellularity (Fig. 8f, g). This effective targeting and activation translated into a robust humoral immune response, with the magnetically-enhanced vaccine eliciting significantly higher titers of OVA-specific IgG, IgG1, and IgG2a antibodies (Fig. 8h–j), and also promoting strong antigen-specific splenocyte proliferation, indicating a potent and lasting cellular immune memory (Fig. 8k).
Repolarization of TAMs (M2) to M1 macrophages in the TME can prevent tumor development and improve tumor models in vivo [192]. Wanga et al. [123], demonstrated the anti-tumor effects of IONPs (SPIO). This name is more common, but you called them IONPs previously conjugated with M2 macrophage-targeted peptide (M2pep) (SPIO-M2pep) based MHT therapy by triggering M2-like macrophages. The anti-cancer and anti-metastatic effects of the SPIO-M2pep + AMF nanosystem were confirmed by decreased body weight (Fig. 9a, b) and several lung metastases (Fig. 9b) in the treated group. Moreover, the lung tissue analysis by H&E staining showed the inhibited lung metastasis in the SPIO-M2pep + AMF group was illustrated (Fig. 9c). Results illustrated the targeting effect of SPIO-M2pep + AMF by decreasing M2 cells (F4/80+ and CD206+) using flow cytometry (Fig. 9d). To evaluate the immune response function, pro-inflammatory and anti-inflammatory cytokines were observed using IF assay in tumor tissues of the cancer model after treatment. The SPIO-M2pep-based MHT stimulated the secretion of TNF-α and IFN-γ in contrast to IL-10 and TGF-β (Fig. 9e).
Liu et al. [193] demonstrated that the liposomes embedded with PEG-coated-Fe2O3 nanoparticles (Lp-IO) enabled ferroptosis activation and combination cancer therapy in vivo using different assays. For this purpose, 4T1 tumor-bearing mice were administered with PBS (NC), DOX, Lp-IO and DOX@Lp-IO for a week (Fig. 10a). The tumor volume decreased significantly in DOX@Lp-IO treated group for 15 days (Fig. 10b). H&E-stained tumor and heart after treatment with DOX@Lp-IO exhibited outstanding necrosis (Fig. 10c). In tumor tissue, the expression of xCT and GPX-4 decreased after treatment with DOX@Lp-IO using IHC staining, which showed the ferroptosis activity in in vivo model (Fig. 10d, e). The Lp-IO system enables intrabilayer generation of hydroxyl radicals (•OH) through a Fenton reaction with hydrogen peroxide (H2O2). This reaction facilitates rapid lipid peroxidation, an essential trigger for ferroptosis. The PEG coating improves liposomal stability and permeability, allowing enhanced penetration of H2O2 and other ROS into the bilayer. This structural design amplifies oxidative stress within tumor cells, creating conditions that promote cancer cell death via ferroptosis while simultaneously providing MRI visibility and pH/ROS-sensitive drug release. The in vivo study demonstrated that mice treated with DOX@Lp-IO exhibited significantly reduced tumor growth compared to other treatment groups. This enhanced efficacy is attributed to the synergistic effects of ferroptosis and chemotherapy. By inhibiting xCT and glutathione peroxidase (GPX-4) pathways, DOX enhances sensitivity to oxidative stress, intensifying the tumor-suppressive effects of ferroptosis induced by Lp-IO.

Ferrite with shell nanoparticle
Magnetic NPs include metal NPs, such as Fe, which can be covered with different materials to improve their biocompatibility and have been approved for application in biotechnology [194]. The therapeutic function of core-shell NPs, especially in the tumor filed, has been evaluated in in vivo studies [195]. Targeting of CSCs for effective cancer treatment (CSCs) was tested following the synthesis of silica shell encapsulating Fe3O4 nanoparticles loaded with heat shock protein inhibitor (HSPI) and conjugated with anti-CD20 (CD20- HSPI&Fe3O4@SiNPs) [196]. After tumor establishment in nude mice, they were treated with different modalities of MNPs and an AMF (Fig. 11a). As shown in Fig. 11b, the tumor-bearing mice treated with CD20- HSPI&Fe3O4@SiNPs and AMP can control the tumor growth better than the control group. H&E staining and TEM images of tumor tissues of mice treated with CD20- HSPI&Fe3O4@SiNPs indicate the necrosis of tumor tissue and the accumulation of MNPs in tumor tissues, respectively (Fig. 11c, d).
Xue et al. [197] synthesized a DOX-loaded magnetic iron oxide alginate-chitosan microspheres (DM-ACMSs), and then evaluated the anti-cancer effect in a mouse model. For this purpose, nude mice were injected with breast cells (MCF-7), and then treated with different MNPs. The mice treated with DM-ACMSs showed a decrease in tumor growth 40 days after treatment compared to the control, MHT, and chemotherapy-treated groups. In addition, histological images confirmed the apoptosis and necrosis of the tumor tissues in mice treated with DM-ACMSs (combined therapy) compared to other treated mouse groups. Totally, these results confirmed the anti-cancer effect of DM-ACMSs in the nude mice model [197]. Additionally, in another study, polymeric nanofibers were used as a shell of MNPs for combating breast cancer. This study develops an implantable electrospun nanofiber mesh for treating drug-resistant breast cancer. The mesh, made of polycaprolactone, co-delivers DOX, curcumin (CUR), and MNPs. It provides sustained drug release for 2 months and enables MHT when exposed to an AMF. Immunohistochemical analysis of tumor sections showed that the synergistic nanofiber mesh treatment significantly modulated key resistance-related proteins. Figure 11e, g reveals a marked reduction of P-glycoprotein (P-gp), a multidrug resistance mediator, in tumors treated with MNPs/DOX/CUR@NFM + AMF, due to sustained curcumin release. Simultaneously, Fig. 11f, h indicates significant suppression of the thermo-resistance protein HSP90 in this group. This dual inhibition enhances tumor sensitivity to chemotherapy and MHT, explaining the superior anti-tumor efficacy observed. It seems that CUR reverses multidrug resistance by inhibiting P-glycoprotein, while hyperthermia enhances chemotherapy efficacy. In vitro and in vivo results demonstrate potent synergistic tumor suppression, overcoming drug resistance effectively. This customizable, low-cost platform offers a promising strategy for localized, long-term combinational thermo-chemotherapy against refractory cancers (Fig. 11i) [198].

In vivo applications of metal magnetic nanoparticles
The utilization of MNPs in vivo has emerged as a promising strategy for targeted cancer therapy and diagnostics. Among these applications, magnetically induced hyperthermia stands out, where nanoparticles generate localized heat under an alternating current magnetic field (ACMF), selectively damaging cancerous cells while sparing surrounding healthy tissues. Mn or Zn ferrite nanocrystals have garnered attention for their dual functionality as both diagnostic contrast agents and effective heat generators [199, 200]. Magnetically induced hyperthermia using Mn–Zn ferrite nanocrystals is a promising cancer therapy and diagnostic approach. Under an ACMF, these nanoparticles generate localized heat, selectively damaging cancer cells [201, 202].
For example, a study by Xie et al. [203] compared passive targeting via the enhanced permeability and retention (EPR) effect with active targeting using RGD-functionalized nanoparticles (MNCs@RGD) that bind integrin αvβ3 on tumor vasculature. MNCs@RGD showed superior tumor targeting, prolonged retention, higher MRI contrast, and enhanced endothelial binding versus PEG-coated nanoparticles (MNCs@PEG). However, thermotherapeutic efficacy improvement was marginal, suggesting that greater nanoparticle accumulation is needed to reach consistent therapeutic temperatures (~43–44 °C). Repeated MNC administration combined with ACMF induced significant tumor apoptosis and inhibited angiogenesis. Despite better targeting, active RGD ligands did not fully solve heat distribution challenges. Mn–Zn ferrite nanoparticles offer a versatile theranostic cancer platform.
However, electroconductive structures like carbon-based nanostructures can effectively improve efficiency of MNPs against cancer [204, 205]. For instance, Matiyani et al. [206] developed a pH-responsive nanocarrier by grafting polyvinylpyrrolidone (PVP) and magnetic Fe3O4 nanoparticles onto graphene oxide (GO-PVP-Fe3O4) for delivering the anticancer drug quercetin (QSR)(Fig. 12a). their results demonstrated a pH-responsive drug release profile of quercetin (QSR) from the GO-PVP-Fe3O4 nanocarrier, demonstrating a significantly higher cumulative release of 35.40% at acidic pH 4 compared to only 15.76% at physiological pH 7.4 over 72 h, which confirms the carrier’s ability to selectively release the drug in the TME (Fig. 12d). This controlled release enhances the therapeutic efficacy, as evidenced in Fig. 12b, c, where the cytotoxicity assessment reveals that the QSR-loaded nanocarrier (GO-PVP-Fe₃O₄-QSR) exhibits a substantially lower IC₅₀ value of 24.20 µg mL−1 against MDA MB 231 breast cancer cells, compared to 49.78 µg mL−1 for free QSR, while showing minimal toxicity to non-tumorigenic HEK 293T cells, even at high concentrations. Further supporting these findings, the phase-contrast microscopic images in Fig. 12e visually confirm the selective anti-cancer activity, where MDA MB 231 cells treated with GO-PVP-Fe₃O₄−QSR show marked morphological changes and reduced cell density, whereas HEK 293T cells retain normal morphology, underscoring the nanocarrier’s biocompatibility and potential for targeted cancer therapy.
Figure 12e presents a typical multifunctional magnetic nanotheranostic agent designed for cancer targeting, diagnosis, and treatment, featuring a superparamagnetic Fe3O4 nanoparticle core that enables MRI contrast and magnetic responsiveness for targeted delivery or hyperthermia. The core is coated with biocompatible materials such as PEG to improve stability and circulation. Functional moieties on the coating include targeting ligands (aptamers or antibodies) for selective tumor receptor binding, therapeutic agents like DOX for controlled release, and diagnostic agents such as fluorescent dyes or radionuclides for multimodal imaging. Also, Fig. 12f illustrates three primary tumor-targeting mechanisms for MNPs to improve cancer treatment efficacy. Passive targeting leverages the EPR effect, allowing nanoparticles to accumulate in tumor tissues via leaky vasculature. Active targeting involves functionalizing nanoparticles with ligands, such as antibodies or peptides, that selectively bind tumor-specific receptors for enhanced uptake. Moreover, magnetic targeting uses an external magnetic field (EMF) to guide and retain nanoparticles at the tumor site, increasing local concentration. These approaches, individually or in combination, enhance targeting specificity and therapeutic effectiveness, advancing precision nanotheranostics in cancer management [207].

Point of view
MNPs, particularly metal-based variants such as iron oxide, cobalt, and nickel ferrites, represent a transformative advancement in cancer therapy. Their unique physicochemical properties—superparamagnetic, biocompatibility, and tunable surface chemistry—enable multifunctional applications, including targeted drug delivery, MRI, and MHT [196]. By leveraging external magnetic fields, MNPs achieve precise tumor localization, minimizing off-target effects and enhancing therapeutic efficacy. For instance, IONPs functionalized with targeting ligands or coated with biocompatible polymers demonstrate controlled drug release within the TME, while their ability to generate localized heat under AMFs induces ICD, synergizing with chemotherapy or immunotherapy.
Preclinical studies underscore the potential of MNPs to overcome limitations of conventional therapies, such as nonspecific cytotoxicity and drug resistance. Tailored designs, such as shell-functionalized MNPs with silica or PEG, improve stability, reduce immunogenicity, and enhance circulation times. Innovations like dual-targeted MNPs combining hyperthermia with checkpoint inhibitors (e.g., anti-PD-L1) have shown remarkable tumor regression and immune activation in murine models. However, challenges persist in optimizing target efficiency, scaling up synthesis, and ensuring long-term biocompatibility.
The clinical translation of MNP-based therapies demands rigorous evaluation of biodistribution, toxicity, and immune interactions. While iron oxide NPs have historical clinical use as MRI contrast agents, newer formulations require validation in complex TMEs. Future advancements hinge on interdisciplinary collaboration to refine nanoparticle design—such as core-shell architectures and stimuli-responsive coatings—and to explore combinatorial therapies (e.g., ferroptosis inducers with immune checkpoint inhibitors). Clinical translation will benefit from robust pharmacokinetic studies and scalable manufacturing processes. MNPs, with their theranostic capabilities, hold immense potential to revolutionize precision oncology, provided these challenges are systematically addressed through innovation and rigorous validation.

Scientific Perspective
From a scientific standpoint, the research on MNPs for targeted drug delivery is a testament to the interdisciplinary nature of modern medical research, integrating nanotechnology, chemistry, and oncology. The adaptability of MNPs, allowing for modifications in size, surface chemistry, and functionalization with various ligands, opens a wide array of possibilities in therapy customization.
Consequently, the application of these nanoparticles in antibody-directed enzyme prodrug therapy (ADEPT) or gene-directed enzyme prodrug therapy (GDEPT) could pave the way for novel approaches integrating physical and biological modalities in oncology [208–212]. Similarly, magnetic nanostructures emerge as promising candidates for addressing infertility—a field grappling with rising prevalence and mechanistic complexity—offering innovative therapeutic platforms for future biomedical applications [213–218]. Additionally, emerging studies demonstrate that electrical stimulation enhances cellular internalization of MNPs through mechanisms such as electroporation [219] These techniques, including pulsed electric fields (PEFs) and tumor-treating fields (TTFields), synergize with MNPs to potentiate their therapeutic impact in both oncological and infectious disease contexts. This synergy could amplify treatment efficacy by coupling nanomaterial targeting with electroresponsive biological effects, as evidenced by recent preclinical advances [220–226].
However, challenges such as ensuring specific tumor targeting, minimizing off-target effects, and optimizing physicochemical properties for efficient drug delivery and release need ongoing research. The document also highlights the importance of understanding the dynamic and complex TME in designing effective nanoparticle-based therapies. Future advancements in this field depend on continued interdisciplinary collaborations, technological innovations, and a deeper understanding of tumor pathophysiology. The promise of MNPs in cancer therapy, therefore, not only lies in their current applications but also in their potential to inspire novel therapeutic strategies and techniques in the future.

Conclusion
The studies reviewed in this document underscore the significant therapeutic potential of MNPs in cancer treatment. Innovative strategies such as dual-targeting and pH-sensitive drug release demonstrate how MNPs can improve therapeutic precision by concentrating drugs in tumor tissues while minimizing off-target effects. The use of both passive and active targeting mechanisms—leveraging the EPR effect and receptor-mediated uptake through functional ligands—highlights the adaptability and specificity of MNPs in interacting with unique features of the TME.
However, further research is essential to fully optimize these nanoparticles for clinical applications. Critical gaps remain in our understanding of the pharmacokinetics, pharmacodynamics, and safety of MNPs, particularly regarding their interaction with immune cells and the broader TME. Moreover, substantial variation in experimental conditions across studies hinders direct comparison of MNPs’ therapeutic efficacy, limiting the potential for meta-analysis and consistent data interpretation. Standardization of experimental parameters, especially in the context of in vivo models, is crucial to advance MNPs from laboratory studies to clinical trials.
In vivo investigations are particularly needed to capture the full complexity of tumor interactions within the host environment, as in vitro studies cannot fully replicate this dynamic. With continued research, collaboration across disciplines, and methodical standardization, MNPs hold promise as a revolutionary tool in cancer treatment, potentially leading to more personalized and effective therapeutic options.