The magnetic gold nanoparticles (mGNP) are hybrid metallic nanocomposites prepared from magnetic and plasmonic moieties that have attracted much attention over the last few years. Magnetic-plasmonic nanoparticles are basically core–shell structures with a bimetallic composition of iron (Fe), cobalt (Co), or nickel ferrite as the magnetic, core and gold (Au), platinum, or silver (Ag) as the plasmonic shell. However, magnetic-plasmonic core–shell structures based on magnetite (Fe₃O₄) or maghemite (ɤ-Fe₂O₃) core and Au shell offer renowned advantages, where the Au shell is coated over the Fe core in a controlled manner [1,2,3]^[1][2][3]. Core–shell nanostructures can also be based on Au and cadmium sulfide, and vice versa, to produce highly stable nanoparticles with semiconductor properties [4,5]^[4][5]. Several reducing and seeding agents are used to form a shell over the core such as citric acid ^[6], sodium borohydride (NaBH₄) ^[7], sodium citrate ^[8], hydroxylamine [9,10]^[9][10], hydroquinone ^[11], L-ascorbic acid ^[12], N,N-dimethylformamide (DMF) and polyvinylpyrrolidone (PVP) ^[13].

The mGNP are synthesized in order to overcome limitations and/or to provide complementary modalities to individual iron oxide nanoparticles (IONP) and gold nanoparticles (GNP) to improve their biological applications [14,15]^[14][15]. In addition to stability and biosafety, mGNP can overcome several challenges of individual IONP and GNP including their optical characteristics (localized surface plasmon resonance and surface-enhanced Raman scattering), conductivity, bio-affinity via thiol/amine terminal group functionalization, and bioavailability, in addition to chemical stabilization of the magnetic core by preventing oxidation, corrosion and aggregation [1,16,17]^[1][16][17].

The mGNP can have several functionalities in a single hybrid nanocomposite structure because of the attachment sites for multiple functional groups. Surface functionalization of mGNP, especially with hydrophilic thiol groups, can render these hybrid nanoparticles more water-soluble and prevent the precipitation and aggregation of nanoparticles [18,19,20]^[18][19][20]. While synthesizing mGNP, their physicochemical parameters including size, morphology, surface charge, and thickness of Au shell must be precisely controlled to avoid their clearance via spleen, liver, and kidney and deliver them to a targeted site such as a tumor.

In addition to the surface modification, the combination of Fe based magnetic and Au based plasmonic materials will further explore biomedical applications for mGNP including targeted drug [21,22^[21][22][23],23], DNA and siRNA [24^{[24][25][26][27][28]},25,26,27,28], hyperthermia [10^[10][29][30],29,30], drug solubility improvement ^[31], detection of protein biomarkers ^[32], PET-MRI (positron emission tomography-magnetic resonance imaging) contrast agents ^[33], and diagnostic or imaging applications for the diagnosis of tumor [19,31^[19][31][34],34], and other diseases [35,36,37]^[35][36][37]. Furthermore, a magnetic field is developed by external magnets to deliver mGNP at a specific targeted site for the desired period as diagnostic or therapeutic agents followed by their eradication from the body. These processes can be observed by CT (computed tomography), MRI (magnetic resonance imaging), and other imaging methods [1,16,25,38]^{[1][16][25][38]}.

The mGNP have been used successfully as carriers for drug and gene delivery applications. Drug delivery systems based on mGNP can have different mechanisms for drug release, for example, Taheri-Ledari et al. [77]^[39] loaded docetaxel into polyvinyl alcohol (PVA) layer over mGNP and utilized it for the treatment of human breast cancer tumors. The temperature-triggered drug release phenomenon occurred by these magneto-plasmonic nanoparticles in normal and cancerous cells as shown in in vitro studiones. Magnetically targeted mGNP indicated drug release due to acidic pH in cancerous cells. Therefore, the combination of pH-controlled and temperature-triggered drug release with magnetically targeted delivery docetaxel makes the mGNP a potential multifunctional drug delivery system. Arora et al. [78]^[40] produced paclitaxel-loaded mGNP with a higher encapsulation efficiency of drug and efficacy against human hepatocellular carcinoma cells.

In a study, mGNP were coated with thiolated PEG followed by the attachment of anticancer DOX through electrostatic interactions. The antitumor effects were obtained by releasing DOX as released in a controlled manner at the tumor site using magnetic targeting and inducing photothermal therapy via using NIR laser radiations. In addition to antitumor effects, the theranostics mGNP were also utilized as contrast agents for MRI in concerned in vivo models. The studyIt was successfully concluded that mGNP can be effectively utilized as MRI contrast agents for guided chemo-photothermal synergistic therapy ^[23].

In another study [79]^[41], mGNP were employed to deliver methotrexate (MTX) to liver carcinoma (HepG2) cells. In Methis study, MTXotrexate (MTX) was covalently attached to mGNP by 2-aminoethanethiol grafting method. They applied external magnetic fields to the nanohybrid system indicating hyperthermia-mediated controlled drug release in an incremental manner. In a study by Elbialy et al. ^[31] mGNP were utilized to reduce the toxicities of DOX in cancerous patients by using a magnetically targeted phenomenon.

For instance, PEI capped mGNP ^[25] can be used for effective biomedical applications of gene and siRNA. Hyaluronic acid was used to target prostate cancer (PC) cells. The prepared HA-PEI-Au/Fe₃O₄ NPs delivered ADAM10 siRNA effectively to suppress the PC3 cell growth and appeared to be biocompatible for intracellular delivery of siRNA. A sSimilar study carried out by ly, Chen et al. [83]^[42] used AU-MNPs to deliver Notch3 siRNA constructed by VEGF RNA aptamer chimera. The obtained complex exhibited much higher silencing efficiency against Notch3 gene in ovarian cancer cells and improved the antitumor effects.

In another study [73]^[43], SPIO-Au mGNP were developed to target MCF-7 (MUC-1 aptamer positive) and CHO (MUC-1 aptamer negative) cancer cell lines. Results showed that the developed formulation had more cellular uptake for MCF-7 cells as compared to CHO cancer cells.

Multifunctional mGNP have been successfully employed for theranostic applications for simultaneous therapy and imaging. Most mGNP show multi-model imaging phenomenon increasing the number of diagnostic tools with convenience and effectiveness. Multifunctional mGNP as a theranostic platform were developed by Feng et al. ^[16] A triple functional agent based on GNR and IONP into PPy. Such an agent (Au/PPy@Fe₃O₄) not only exhibited high contrast for MRI and CT imaging but also showed cytotoxicity by photothermal effects.

For Fe₃O₄@SiO₂-PrNH₂@Au, APTES was used to functionalize mGNP that were used as MRI and CT scan contrast agents in human hepatocellular carcinoma [84]^[44]. Sodium citrate-based Fe₃O₄@Au mGNP ^[2] were developed as MRI and CT scan contrast agents by Mohajer et al. Fe/Fe₃O₄ PrNH₂@Au were synthesized as bifunctional magnetic plasmonic nanostructures for applications in MRI and magneto-optical thermal therapies [85]^[45]. Reguera et al. [57]^[46] also developed Fe₂O₃@Au Janus magnetic-plasmonic nanoparticles for photoacoustic imaging, MRI, and CT scan contrast agents.

During the last decades, the Au coating has been suggested for contrast enhancement over magnetic nanoparticles for MRI. The iron coating as a contrast agent over Fe NPs imparts attractive features to the multi-layered NPs for MRI exhibiting up to 200 times improved field relativity (r1  =  3.0 mM⁻¹ s⁻¹ to 585 mM⁻¹ s⁻¹). Scientists reported that AuNPs coating over Fe NPs can be used to attach to hundreds of ligands and to carry gadolinium chelates to further enhance contrast capabilities with improved anti-tumor targeting, imaging, and immunotherapy [86]^[47].

The mGNP can be potentially developed for use in the diagnosis of various diseases and in vivo detection of drugs utilized for the treatment of diseases. For instance, a lateral flow immunochromatographic assay system was developed for the detection of immunoglobulin M (IgM) related to TORCH infections (T-toxoplasmosis, O-other agents, R-rubella, C-cytomegalovirus, and H-herpes simplex virus) based on mGNP [87]^[48]. IgM antibodies to four types of pathogens were detected using the constructed device and displayed higher sensitivity. The mGNP showed 100% sensitivity and 100% selectivity in 41 seropositive and 121 seronegative samples. Another study against HBV was conducted by Mashhadizadeh et al. [88]^[49] who prepared an mGNP modified with a carbon paste electrode for immobilization of thiol modified HBV probe DNA and determined its trace amount. The proposed DNA biosensor could measure HBV DNA concentration with a low detection limit of 3.1 (±0.1) × 10⁻¹³ M, much lower than the detection limit reported with GNP or MNP alone. ThisIt work was successfully utilized for sensitive detection of HBV target in urine and blood plasma.

Besides application in the treatment of cardiovascular diseases, mGNP have also been utilized in the detection of cardiac markers and cardiac drugs. Gold-coated MNPs [80]^[50] were used as electrochemical immunosensor for digoxin (Fe₃O₄-Au-NPs). The developed immunosensor was able to detect digoxin with a detection limit of 0.05 ng mL⁻¹. The studyone concluded that the proposed method had acceptable reproducibility, stability, and reliability upon detection of digoxin in serum samples.

Due to the slow rate of axonal regeneration [82]^[51], neuro-regeneration is one of the most significant challenges in neuroscience. Extensive studiones employed in the last decade were targeted at increasing the speed of neuron recovery. Many efforts have been made to develop molecules [89]^[52], proteins [90]^[53], biomaterials [91]^[54], and growth factors [92]^[55] that possess the ability for axonal regrowth. The pharmacological effects of such agents require them to be released continuously intracellularly [93]^[56] and require easy transport through the blood–brain barrier (BBB) [82]^[51]. Although MNP have been demonstrated as effective carriers for neuro-regenerative agents, the direct use of uncoated MNP possess challenges of instability in the neuronal environment, aggregation [82]^[51], and cellular toxicity [94]^[57]. Hence, they have been protected by coating materials including Au. mGNP have been used as a carrier for efficiently transporting neuro-regenerative agents across BBB to enhance the half-life and efficiency in promoting neuronal growth. Recently, Yuan et al. employed the use of MNP coated with Au for precise control of neuro-regeneration towards PC-12 cells. They developed Au-coated MNP functionalized with NGF (nerve growth factor) by dynamic magnetic field technique. Cells treated with NGF-IO-Au NPs were studiedknown for cellular uptake and cell viability. The results confirmed that dynamic magnetic field performed better in neuro-regeneration than static ones. Experimental data was also confirmed by cytoskeleton force model to predict the neurite elongation and orientation [82,95]^[51][58].

Similarly, other research conducted more recently by Yuan et al. [93]^[56], reported the development of mGNP conjugated with porous coordination cages for controlled drug release in neuro-regeneration in PC-12 cells. The pyrene-PEG-SH bridge enabled functionalization of mGNP with PCC-3 and resulted in higher interaction with PC-12 neuron-like cells. With negligible toxicities, IO-Au-RhB-PCC-2(3) nanocarrier exhibited effective drug loading of retinoic acid (RA) and controlled release using low-intensity LED lights.

Chen et al. [96]^[59] reported the development of PEG-coated mGNP modified with insulin targeted to brain cells. They found out that the concentration of developed formulation using the physiologically based pharmacokinetic model, advection-diffusion equation, and COMSOL multiphysics. The results showed good permeability, in vivo bio-distribution, and bioavailability of 24.47% which further improved bioavailability by 3.91% under SMF.

Most recently, in 2022, mGNP were studiedknown for modulating neuronal excitability and outgrowth [81]^[60]. Static magnetic field stimulation gold-coated MNP were assessed for effects on brain physiology and it was found that SMS enhanced brain uptake of mGNP, delayed blockade, reduced frequency, and decreased Ca²⁺ fluxes amplitude at L-type voltage-gated Ca²⁺ channel (VCGG). Thus, by modulating VGCC, SMS-IO-Au mGNP can be used for neuronal outgrowth and as a drug delivery strategy to treat Parkinson’s disease.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with joint inflammation resulting in cartilage and bone damage leading to systemic complications. It is important to assess the long-term effectiveness and safety of RA therapies. Nanotechnology-based interventions and strategies help overcome challenges associated with conventional medicines such as low solubility, permeability, penetrability, poor bioavailability, systemic toxicity, poor ligand-target interaction producing sub-therapeutic response [97,98,99]^[61][62][63].

Recently, a published studyone served as proof for use of mGNP as an attractive alternative for future treatment of rheumatic diseases. The studyIt was aimed at the use of mGNP as magnetically targeted to the arthritic articulation of collagen-induced arthritis (CIA) [100]^[64]. The mGNP led to significant clinical improvements i.for example., suppresses joint edema, infiltration by leukocytes, inflammation as well as TNF-α (tissue necrosis factor-α) and IL-β (interleukin-β) expression in synovium accompanied by lack in toxicity. Another study^[36] [36] carried out for the chemo-photothermal treatment of RA was conducted on MTX-loaded PLGA/Au-/Fe mGNP followed by conjugation of arginine-glycine-aspartic acid (RGD) with a second layer of Au being applied on Fe layer to prepare MTX loaded PLGA/Au-/Fe/Au-RGD. Upon application of magnetic field, local heat generated at inflammation region and MTX release from mGNP is accelerated. They also enable in vivo T2-MRI. Besides that, they when combined with NIR irradiation and external magnetic field, mGNP retention can be enhanced.

Many tumors express heparanase as the tumor-related antigen. Recently, a group of scientists developed heparanase targeting Au-Fe nanoparticle probes (30 nm). The Au-Fe NPs worked as a contrast agent and were functionalized with heparanase monoclonal antibodies to target cancer cells. This antitumor immunotherapy approach using 3.0 T MRI showed the effectiveness of these nanoprobes for identifying metastasis by observing reduced T2WI signals during magnetic resonance imaging (MRI). The heparanase functionalization on the surface of Au-FE NPs showed enhanced antitumor targeting to reduce off-target toxic effects [101]^[65].