Bio-magnetic nanomedicine for targeted drug delivery of breast cancer: green synthesis, functional design, and translational challenges

Abstract

Breast cancer is an increasing cause of morbidity and death globally. The conventional chemotherapy and ligand-based nanocarriers approaches are facing challenges due to treatment resistance, tumor heterogeneity, and off-target toxicity. In this context, bio-magnetic nanomedicine has emerged as a revolutionary approach, utilizing magnetic nanoparticles for precise drug delivery that goes beyond passive enhanced permeability and retention (EPR) processes. This review investigates the relationship of green synthesis, functional design, and translational issues in the development of bio-magnetic nanocarriers for breast cancer treatment. First conceptual progression of iron oxide contrast agents to field-guided treatment systems are discussed, with a focus on anatomical and microenvironmental limitations specific to breast cancers. Eco-friendly nanoparticle manufacturing, including approaches supported by microbes and plants, receives attention because it improves biocompatibility, lowers oxidative cytotoxicity, and modifies magnetic and theranostic performance. Chemotherapy, hyperthermia, and immunotherapy are among the multimodal therapeutic applications made possible by advanced core-shell designs, tumor-specific surface functionalization, and magneto-responsive drug release techniques, such as AND-gate activation. This review highlights the nano-bio-magnetic interaction, imaging-guided theranostics, and biosafety issues related to iron homeostasis, ferroptosis, and the relative importance of green-synthesized approaches. Finally, translational and clinical challenges such as magnetic field penetration, large scale manufacturing, regulatory pathways, and emerging trends are discussed. In these trends magnetically guided nanorobots, exosome based delivery, and personalized patient-derived tumor models are critically examined. Collectively, this review highlights bio-magnetic nanomedicine as a precision navigation platform, integrating functional design, eco-sustainability, and clinical foresight to advance breast cancer therapy.

Graphical abstract

Introduction

Cancer is remains one of the leading causes of mortality worldwide, accounting for millions of deaths annually [1–3]. Among various types of cancer, breast cancer is one of the most common malignancies in women worldwide. Despite significant advances in diagnosis and treatment, it greatly contributes to cancer-related death. Over 2.3 million cases of breast cancer are diagnosed globally each year. It revealed a persistent and rising healthcare burden in a range of socioeconomic domains [3, 4]. The significant heterogeneity of breast cancer, which includes hormone receptor positive, HER2-positive, and triple-negative subtypes, each with specific genetic markers, metastatic behavior, and treatment limitations, further increases the clinical complexity of the disease. Long-term therapeutic efficacy is ultimately limited by this heterogeneity, which results in varying treatment responses and plays a significant role in both intrinsic and acquired drug resistance [5]. Chemotherapy is a major component of conventional cancer treatment, but its therapeutic efficacy cancer remarkably compromise due to complexity and heterogenicity cancer [6–8]. Despite their potential efficiency, these regimens are often related to serious off-target toxicity because of nonspecific drug biodistribution, which can lead to cardiotoxicity, myelosuppression, neurotoxicity, and a worse quality of life. Moreover, systemic toxicity frequently limits the dosage escalation to overcome tumor resistance, resulting in less than ideal tumor exposure. Nanomedicine based drug delivery approaches were designed to overcome these limitations by permitting controlled release, increasing the solubility of hydrophobic drugs, and improving pharmacokinetics. In preclinical breast cancer models, ligand-functionalized nanocarriers targeting receptors such as the estrogen receptor (ER), HER2, and CD44 have demonstrated enhanced cellular uptake. However, variable receptor expression, receptor saturation, adaptive tumor growth, and competition with endogenous ligands have all hindered the practical translation of ligand-based nanocarriers, undermining consistent targeting efficiency [9, 10]. In addition to receptor-related problems, the majority of therapeutically studied nanomedicines rely on the enhanced permeability and retention (EPR) impact for tumor formation. The EPR effect is well-established in animal models, but there is growing doubt about its applicability in therapeutic settings. The vascular permeability, stromal density, and interstitial fluid pressure of human tumors vary greatly, which leads to uneven nanoparticle extravasation and intra-tumor penetration. The limits of passive targeting techniques are highlighted by thorough assessments of nanoparticle delivery efficiency, which have revealed that, on average, less than 1% of the injected nanoparticle dosage penetrates solid tumors [11, 12]. Due to these limitations, there is more interest in externally regulated delivery methods that can achieve patient-adaptable and spatially accurate medication targeting.

In order to actively target therapeutic molecules to tumor locations, bio-magnetic nanomedicine has developed as a potent multidisciplinary approach that combines nanotechnology, magnetic physics, biophysics, and oncology. External magnetic fields may be employed to manage magnetic nanoparticles, most typically iron oxide-based systems, to accomplish guided movement, localized accumulation, and extended retention within malignancies. Unlike passive nanocarriers, magnetically responsive systems enable real-time spatial control over nanoparticles distribution, largely independent of tumor vascular permeability or receptor expression [13]. This characteristic is particularly useful for breast cancer since the tumor’s location and anatomical accessibility enable the application of an external magnetic field. Beyond localized accumulation magnetic nanoparticles also exhibits therapeutic potential. Under alternating magnetic fields, these devices can produce localized heat, enabling magnetic hyperthermia that induces immunogenic cell death or enhances the susceptibility of cancer cells to therapeutic interventions. Furthermore, bio-magnetic nanomedicine has been proposed as a promising theranostic platform due to its intrinsic magnetic properties that allow for simultaneous diagnostic imaging utilizing magnetic resonance imaging (MRI) [14–17]. Collectively, these characteristics transform magnetic nanoparticles from passive carriers into potentially dynamically controlled therapeutic systems. The surface chemistry and synthetic origin of magnetic nanoparticles play an important role in determining their biological destiny, regardless of how magnetic targeting overcomes a number of biological limitations. Toxic solvents, surfactants, and severe reaction conditions are frequently used in chemical synthesis techniques, which can lower biocompatibility and produce environmental issues. The best alternates are green synthesis methods that use biomolecules, microbial systems, enzymes, and plant extracts. These ecologically friendly techniques usually provide nanoparticles that improve cellular interactions, decrease immunogenicity, and enhance colloidal stability [18–20]. Particular, green synthesis extends beyond environmental sustainability as it can significantly influence the biological interactions of nanoparticles. Biomolecules based surface coatings can change the cellular absorption routes, intracellular movement, and protein corona formation, which affect therapeutic efficiency and the safety. Studies exhibited the potential superiority of green-synthesised magnetic nanoparticles for biomedical applications that shows improved hemocompatibility, reduced oxidative stress (ROS), and enhanced tumor cell internalization [21]. Despite the rapid advancement in green synthesis and magnetic targeting, present literature is still dispersed. Many studies focus on different aspects nanoparticle synthesis, magnetic hyperthermia, or imaging applications without systematically connecting environmentally friendly synthesis techniques to drug delivery efficiency, and translational feasibility. Moreover, translational issues like long-term biosafety, clinical implementation of magnetic field systems, large scale production of green synthesized nanoparticles, reproducibility of magnetic properties, and regulatory approval of drug-device combinations are usually discussed related to breast cancer [22–24].

So this study is aimed to provide a comprehensive and integrated investigation of bio-magnetic nanomedicine for targeted drug delivery in breast cancer. This review focuses on recent advances in magneto-responsive drug release, rational functional design for breast cancer targeting, and green synthesis of magnetic nanoparticles. It provides a comprehensive analysis of synthetic, biological, and regulatory challenges to clinical translation. By addressing these challenges it bridge the gap between nanotechnology innovation and clinical oncology, demonstrating bio-magnetic nanomedicine as a precision-guided therapy paradigm.

Green synthesis of magnetic nanoparticles for breast cancer applications

Green synthesis of magnetic nanoparticles (MNPs) is cost-effective and efficient alternatives to conventional chemical and physical processes, particularly for therapeutic applications. Traditional synthesis approaches usually require harsh conditions and produce hazardous residues and reduce biocompatibility. Green synthesis requires mild and environment friendly conditions using biological resources. This approach produce MNPs with unique physicochemical characteristics including, variable size, surface functionality, and enhanced interactions with biological systems [18].

Plant‑based green synthesis

In plant extract based, various phytochemicals including, flavonoids, terpenoids, anthocyanins, phenols, and alkaloids present in extracts serve as both stabilizers and reducing agents. These biomolecules can regulate the nucleation and growth of particles, leading to the formation of an intrinsic biocompatible surface layer that improves colloidal stability and minimize aggregation [25]. It is reported that plant based synthesis of magnetic iron oxide nanoparticles (MIONPs) produces appropriate size of nanoparticles in the range of 20–30 nm. As the precise biodistribution and effective magnetic responsiveness under external magnetic fields depend on particle size [26, 27]. Surface capping organic compounds mostly effect the saturation magnetization (Ms), which are essential for effective magnetic guidance and hyperthermia responses [28].

Additionally, phytochemical layers offer a natural capping layer that could decrease immune recognition and reduce the need for synthetic polymers. In the acidic tumor microenvironment, this coating also acts as a reservoir for further functionalization with drugs or targeting ligands, improving drug loading and regulated release kinetics which is important factor for efficient delivery to breast cancer cells [29]. To illustrate a potential synergy between bioactive plant chemicals and nanoparticle carriers for therapeutic applications, iron oxide nanoparticles produced using Brassica oleracea (red cabbage) peel extract demonstrated significant lethal effects on MCF-7 breast cancer cells [30]. Figure 1 shows the synthesis of chitosan-coated magnetic nanoparticles (CCMNPs). In this study black pomegranate peel extract (BPPE) was used as an anticancer agent and incorporated into nanocomposites to provide a therapeutic strategy for breast cancer. Using MDA-MB-231 and 4T1 breast cancer cell lines, with NIH/3T3 as a normal fibroblastic cell line, the cytotoxicity of black pomegranate peel extract loaded chitosan-coated magnetic nanoparticles (BPPE-CCMNPs) was evaluated [31].

Fig. 1.

Synthesis and cytotoxicity evaluation of black pomegranate peel extract–loaded chitosan-coated magnetic nanoparticles (BPPE-CCMNPs) in MDA-MB-231 and 4T1 breast cancer cell lines, with NIH/3T3 fibroblasts as the normal control [31]

Microbial and biomolecule‑assisted synthesis

Microbial systems and isolated biomolecules provide alternative green synthesis techniques with distinct advantages. Due to precise biomineralization processes, magnetotactic bacteria (MTB) naturally create biogenic magnetosomes, which are membrane-bound magnetic nanocrystals with a restricted size distribution and great magnetic homogeneity. These biologically produced magnetosomes have superior magnetic properties, uniform morphology, and native lipid-protein shells and easily functionalized for drug delivery systems [32]. In addition to magnetotactic bacteria, enzyme‑mediated approaches use proteins or catalytic biomolecules to nucleate and grow magnetic iron oxide cores under controlled conditions. These processes can yield particles with enhanced colloidal stability and improved functionalization potential due to native protein or polysaccharide coatings that are recognized as self by immune systems, thereby reducing uptake by macrophages and prolonging circulation times. Moreover, these biologically derived coatings can reduce non‑specific adsorption of serum proteins, a phenomenon known as the protein corona, which can alter nanoparticle behavior in vivo and affect biodistribution and cellular uptake [33]. Table 1 shows the different green synthesized MNPs for breast cancer applications.

Table 1.

Comparative studies green synthesized MNPs for breast cancer therapy

Nanomaterial name	Green source	Breast cancer type	Target cell	In vivo PK / biodistribution	Notes versus doxil	References
MIONPs	EGCG and BSA (green route)	Drug delivery, antiproliferative	MCF-7, T47D			[34]
MIONPs	Turmeric rhizome extract	Cytotoxicity evaluation (breast)	MDA-MB-231	-	-	[35]
MIONPs	Brassica oleracea	Cytotoxic and anti-migrative	MCF-7	-	-	[30]
Fe NPs	Satureja hortensis essential oil	Anticancer screening	MCF-7	-	-	[36]
MIONPs	Mentha longifolia extract	Nanocarrier design, release studies	(pH-dependent release)	-	-	[37]
Mg-Co Ferrites NPs	Curcuma longa (turmeric)	Cytotoxic evaluation	MCF-7	-	-	[38]
α-Fe₂O₃ NPs (Ag-doped)	Green route (plant extract)	Cytotoxicity on MCF-7	MCF-7	-	-	[39]
Fe₃O₄@chitosan-DOX	Green-coating (biogenic)	Chemotherapy enhancement	MDA-MB-231	-	-	[40]
MIONPs	Albizia adianthifolia leaf	Cytotoxicity studied	MCF-7, AMJ-13	-	-	[41]
MIONPs from Bacillus megaterium	Bacterial biomimetic synthesis	Hyperthermia & drug delivery evaluation	Hyperthermia; drug carrier support	t₁/₂ ~ 3.5 h	Shorter than Doxil (t₁/₂ ~55 h)	[42]
Magnetosome protein-mediated BMNPs	Magnetosome protein biomineralization	4T1 & MCF-7 tumors (mouse model)	Targeted chemotherapy & hyperthermia	t₁/₂ ~ 6 h	Faster clearance vs. Doxil	[43]
Biomimetic cell membrane-coated Fe-functional NPs	Tumor cell membrane biomimetic coating	Breast cancer targeting	Targeting & MRI	t₁/₂: 8 h	Enhanced tumor accumulation	[44]
Chitosan-coated magnetic NPs baseline	Chitosan biomolecule coating	MDA-MB-231 & 4T1 cells	Cytotoxicity/selective cell death	-	-	[31]
Magnetosome chains from Magnetospirillum	Microbial magnetosomes	Breast cancer cell lines (hyperthermia)	Hyperthermia targeting	-	-	[45]
Magnetosome-like MNPs via MTB protein Mms6	Biomolecule (Mms6) guided synthesis	Tumor mouse model	Enhanced magnetic enrichment	t₁/₂: 5 h	Improved targeting	[46]
Chitosan-functional MNPs and Doxorubicin	Chitosan biomolecule	Ehrlich solid tumor (BC model)	Enhanced antitumor efficacy	t₁/₂: 4.2 h	Faster than Doxil	[47]
Poly(amino acid)-coated iron oxide	Biomolecule coating	Breast cancer imaging	MRI contrast & targeting	-	-	[48]
Magnetosome review on therapy mechanisms	MTB magnetosomes	Cancer therapy incl BC	Targeting/hyperthermia	-	-	[49]
EMT66-DOX covalent functional MNPs	DMSA biomolecule functionalization	MDA-MB-231 CSCs & primary BC	Breast CSC targeting	-	-	[50]

t₁/₂ = plasma half-life

Functional superiority of green‑synthesized magnetic nanoparticles

The green synthesized MNPs provide a number of practical advantages when involved in nanomedicine platforms for breast cancer administration. Protein adsorption patterns in biological fluids can be modulated by organic layers produced by microbes or plants, which may reduce opsonization and accelerate the mononuclear phagocyte system’s clearance. This results in a more regulated biomolecular corona in some systems, which improves circulation and reduces excessive immune activation [33]. Target cell internalization rates can be increased by biogenic coatings and surface phytochemicals interacting effectively with cellular membranes or even particular surface receptors. This impact was shown numerous green-synthesised metal and metal oxide nanoparticles applied to cancer cells [51]. Because green synthesized nanoparticles produce fewer radicals during synthesis and have antioxidant phytochemicals on their surface. So, they frequently cause less oxidative stress in non-target cells than their chemically synthesized particles. This characteristic is especially important for breast tissue since it may significantly improve therapeutic indices by reducing collateral damage to healthy mammary cells [52].

Magnetic performance of green-synthesized magnetic nanoparticles compared with conventional chemical routes

In green synthesis approaches usually microorganisms, plant extracts, or biological metabolites are used as reducing and stabilizing agents. These offer advantages as compared to chemical synthesis including environmental sustainability, low toxicity, and better biocompatibility. However, some studies showed that the presence of organic biomolecules on the surface of nanoparticle can somewhat decrease magnetic performance. This decrease in magnetic performance is attributed to surface spin disorder or non-magnetic coating layers. For instance, plant extracts based synthesized magnetite nanoparticles exhibited decreased Ms compared to the particles synthesized by chemically approaches. This is due presence of capping agents (organic molecules) that decrease the magnetic core and influence crystallinity [53, 54]. In the chemical synthesis approaches including thermal decomposition, co-precipitation, or polyol synthesis, better control over crystal growth. As a result the nanoparticles with phase purity usually have higher magnetic susceptibility. Bulk magnetite typically shows Ms values in the range of 90 to 100 emu g⁻¹, whereas nanoscale magnetite synthesized through different routes often shows lower values due to surface covering and reduced crystallinity [55]. Moreover, recent studies highlights that optimized green synthesis approaches can produce magnetite nanoparticles with magnetization values approaching those of chemically synthesized materials. For example, glutathione-mediated green synthesis of Fe₃O₄ nanoparticles have a Ms of 85.4 emu g⁻¹, which is comparable to nanoparticles synthesized by chemical synthesis [56]. Furthermore, plant based synthesis approaches have reported superparamagnetic iron oxide nanoparticles with Ms values exceeding 50 to 70 emu g⁻¹. these studies highlights that the optimized green synthesis conditions can also produce magnetically responsive materials suitable for biomedical applications [57]. The comparision of Ms values of magnetic nanoparticles synthesized by chemical and green approaches is given in Table 2.

Table 2.

Comparison of saturation magnetization values of magnetic nanoparticles synthesized by chemical and green approaches

Synthesis method	Nanoparticle type	Saturation magnetization (Ms)	Key observation	References
Chemical co-precipitation	Fe₃O₄ nanoparticles	50–90 emu/g; bulk ≈ 92 emu/g	High crystallinity and strong magnetic response	[58, 59]
Green synthesis (plant extract)	Fe₃O₄ MIONPs	~ 50–70 emu/g	Organic capping layers may reduce magnetization	[26]
Green synthesis (microbial reduction)	Fe₃O₄ nanoparticles	~ 70–75 emu/g	Biosynthesis can approach chemical magnetization levels	[57]
Green synthesis using glutathione	Fe₃O₄ nanoparticles	~ 85 emu/g	Comparable magnetization to chemical synthesis	[56]

Functional design of bio-magnetic nanocarriers

It is important to precisely integrate magnetic responsiveness, biological compatibility, surface targeting, and environmentally driven drug release when developing bio-magnetic nanocarriers for targeted breast cancer therapy. The main synthesis techniques that improve the performance of magnetic drug delivery systems are core–shell topologies, targeted surface functionalization, and magneto-responsive release mechanisms.

Core-shell magnetic architectures

A fundamental design for magnetic nanocarriers is core-shell architecture, usually comprising an organic or inorganic shell surrounding a super paramagnetic iron oxide (SPIO) core to enhance drug loading capacity, stability, and biocompatibility. MIONPs exhibit low toxicity, excellent chemical stability, and great magnetic responsiveness making them ideal as magnetic cores for biomedical applications including drug delivery and hyperthermia treatment. Previous studies demonstrate that coating magnetic cores such as chitosan, dextran, polyethylene glycol (PEG), and poly(lactic-co-glycolic acid) (PLGA) enhance the colloidal stability, decreases immune recognition, and increases circulation time in vivo [60]. Additionally, polymeric shells act as reservoirs for therapeutic molecules, allowing for maximum drug loading and preventing early release. When combined with thermo-responsive polymers these coating enables temperature-controlled release upon exposure to localized heating under an alternating magnetic field (AMF). Lipid-based shells and magneto-liposomes have been shown to enhance the dual loading and biocompatibility of both hydrophilic and hydrophobic drugs. Additionally, biomimetic coatings derived from cell membranes or extracellular vesicles have emerged as advanced shell materials that take advantage of immune evasion and intrinsic targeting abilities to improve tumor accumulation reduce clearance [61]. Moreover, the shell composition and thickness strongly influence both biological interactions and magnetic responsiveness. Thicker shell can enhance drug loading but decrease magnetic saturation and responsiveness which decreases the efficiency of external magnetic guiding. Conversely, thinner shells preserve magnetic sensitivity and structural stability, and controlled release efficiency is decreased. Therefore optimizing core-shell dimensions is important to balance magnetic performance with stability and efficiency of drug delivery in breast cancer models [62].

Breast cancer-targeted surface functionalization

Surface functionalization is important to enhance cellular uptake and tumor selectivity. In breast cancer therapy, functionalizing magnetic nanocarriers with ligands that recognize molecular markers overexpressed on cancer cells such as estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and cluster of differentiation 44 (CD44) enhances internalization and therapeutic outcomes [63]. Active targeting ligands include monoclonal antibodies or antibody fragments, small peptides, aptamers, and carbohydrates that bind selectively to overexpressed receptors. For example, hyaluronan (HA), a natural ligand for CD44, has been successfully conjugated to iron oxide nanoparticles to facilitate receptor-mediated uptake in CD44-rich breast cancer cells, improving specificity and internalization efficiency [64]. As breast tumors show molecular heterogeneity, single-ligand targeting can be insufficient. Dual-targeting strategies, combining magnetic guidance with receptor-specific ligands or multiple ligands, have demonstrated synergistic improvements in tumor accumulation and therapeutic efficacy. Such systems leverage an external magnetic field to concentrate nanocarriers at the tumor site while ligands facilitate enhanced cellular uptake and retention, overcoming receptor variability across tumor cells. Recent studies have demonstrated multifunctional nanodrug systems where magnetic targeting and biomimetic coating (e.g., tumor cell membranes) are both used to elevate accumulation and specificity, achieving robust antitumor effects while minimizing off-target toxicity [61]. Additionally, recent experimental evidence indicates that applying external magnetic fields can enhance the uptake of chemotherapeutic agents in breast cancer cells by increasing cellular internalization, a phenomenon linked to magnetically influenced transport mechanisms that improve drug internalization efficiency [65]. Table 3 shows the core-shell and surface functionalized bio-magnetic nanomaterials developed for targeted drug delivery and theranostic applications in breast cancer.

Table 3.

Surface-functionalized bio-magnetic nanomaterials for targeted drug delivery and theranostic applications in breast cancer

Nanomaterial	Core-shell/ functionalization	Breast cancer application	Targeting cell/marker	In vivo PK / biodistribution	Notes versus doxil	References
Magnetic Solid Lipid Nanoparticles (mSLNs)	Lipid shell	DOX delivery to breast cancer cells	MCF-7 cytotoxic targeting	t₁/₂ ~ 2 h	Shorter circulation vs. Doxil	[69]
Fe₃O₄ @ SiO₂ coated magnetic NPs	Silica shell	DOX delivery to MCF-7	MCF-7 cytotoxic targeting	-	-	[70]
Supported lipid bilayer on Fe₃O₄-SiO₂ NPs	Lipid bilayer	DOX internalization in MCF-7	MCF-7 uptake	-	-	[71]
Iron oxide NPs with albumin, anti-VEGF, DOX	Protein/PEG shell, antibody	Targeted delivery & MRI	VEGF receptor	t₁/₂ ~ 7 h	Faster than Doxil	[72]
CD44-targeted lipid-polymer hybrid NPs	Lipid/HA functional	Anti-BC effect	CD44 receptor	-	-	[73]
Core–shell Fe₃O₄@MoS₂@mSiO₂ with FA, DOX	Core–shell hybrid	MRI, chemo/PTT	Folate receptor and MDA-MB-231	t₁/₂ ~ 6 h	Faster than Doxil	[74]
Iron oxide PEG-pluronic-stabilized	Polymeric PEG shell	DOX/paclitaxel synergy BC cells	MCF-7 targeted via EPR	t₁/₂ ~ 5 h	Shorter than Doxil	[75]
Magnetic polymeric nanocarrier HA functional	HA polymer	CD44-mediated endocytosis	CD44, BC cells	-	-	[76]
RBC membrane coated magnetic NPs	Biomimetic coating	Reduced immune clearance	EpCAM, MCF-7	t₁/₂ ~ 12 h	Improved retention	[77]
Folate-conjugated magnetic micelles	Folate ligand, polymer	Folate receptor targeting	MDA-MB-231	-	-	[78]
Magnetic lipid hybrid NPs with DOX	Lipid polymer hybrid	Chemo targeting	Tumor cells	-	-	[79]
Targeted magneto-hyperthermia carriers	Polymer/shell coatings	Hyperthermia, chemotherapy	BC cells	-	-	[80]
MION-polymer conjugates with DOX	Polymeric coating	Drug delivery MCF-7	MCF-7 & MDA-MB-231	t₁/₂ ~ 3.8 h	Faster than Doxil	[81]
PEI-coated MIONPs, DOX	PEI functionalization	Enhanced uptake in resistant cells	Resistant BC	-	-	[82]

t₁/₂ = plasma half-life

Physical limitations of magnetic field gradients in clinical magnetic targeting

The interaction between the carrier (particles) magnetic moment and externally supplied magnetic field gradients allows drug-loaded nanoparticles to be guided magnetically. The product of the magnetic moment and the spatial gradient of the magnetic field may be used to represent the magnetic force acting on a nanoparticle. Therefore, substantial magnetic field gradients at the tumor location and high particle magnetization are required for efficient targeting. Significantly, the magnetic field intensity produced by permanent magnets rapidly reduces with distance, roughly following an inverse-cube relationship with regard to the distance between the magnet and the target tissue. Consequently, when the tumor depth increases, magnetic forces drastically decrease. This physical constraint is an important challenge for clinical translation of magnetic drug targeting systems [66]. According to theoretical and experimental research, the external magnetic targeting is usually most successful for cancers near the body surface. The early clinical and preclinical studies highlights that, the magnetically guided nanoparticles might successfully aggregate in tumors within about 5 mm of the body surface, while targeting efficacy significantly drops at deeper depths. According to calculations, depending on particle size and magnetic susceptibility, nanoparticles with typical magnetic qualities can only be successfully steered to tissues that are around 1–2 cm from the magnet surface. These results demonstrate the inherent constraints imposed by quick magnetic field strength degradation in biological tissues [67]. This challenge is especially important for breast cancer treatment because tumor depth varies greatly based on the body composition of patient and anatomical location. Deeper lesions and metastatic deposits in axillary lymph nodes may be subject to much lesser magnetic pressures than superficial breast cancers or lesions close to the surface. In these cases, conflicting physiological forces, such as hydrodynamic drag from blood flow and interstitial pressure within tumor tissues, must be overcome by the magnetic attraction applied to nanoparticles. The capacity of external magnets to efficiently collect circulating nanoparticles at deeper tumor locations is further decreased by these biomechanical limitations [66]. Many approaches have been proposed to reduce these physical limitations. One of them is the application of stronger magnets or optimized magnet geometries capable of generating higher field gradients. For example, neodymium-iron-boron (NdFeB) permanent magnets (produce relatively strong fields) are commonly applied in experimental magnetic targeting systems. Even with these magnets, field strength and gradients reduce significantly with depth, limiting the ability to target tumors located several centimeters below the skin surface [68]. In order to create localized high-gradient magnetic fields at deeper anatomical regions, other strategies are applied such as magnetizable stents, implanted magnetic materials, or internally located magnetic seeds., These methods more complex and possible surgical risks, despite the fact that they can greatly improve nanoparticle capture in deep tissues. As a result, research into the clinical viability of magnetically guided nanomedicine for deep tumors is still ongoing and requires for multidisciplinary developments in materials engineering, clinical oncology, and magnetic device design.

Magneto-responsive drug release mechanisms

A distinct strength of bio-magnetic nanocarriers is in their ability to respond to external stimuli, enabling controlled and on-demand drug release at the tumor site. Among the most widely studied triggers is the AMF, which induces localized heating of magnetic nanoparticles through Néel and Brownian relaxation processes at frequencies typically in the range of 100–500 kHz, enabling controlled thermally triggered drug release. This heat can be used to quickly release drugs from thermally sensitive carriers and initiate MHT, providing temporal control over therapeutic effect [83]. Heat produced by magnetic cores under an AMF can cause thermal-responsive polymer shells or lipid matrices to break down, resulting in rapid release of drugs at the exact site of the tumor. At moderately hyperthermic temperatures (~ 40–45 °C), thermoresponsive materials like poly(N-isopropylacrylamide) (PNIPAAm) show phase transitions that allow for the quick collapse of the polymer structure and the distribution of encapsulated medications upon AMF activation. This suggested that a highly controlled release profile is supported by AMF-induced thermal transitions, optimizing drug activity while minimizing systemic exposure [84]. Figure 2 shows the integrated iron oxide nanoparticles (γ-Fe₂O₃) in thermoresponsive lipid nanoparticle (TLN) to generate hyperthermia by externally applied AMF pulses [83]. Beyond thermal mechanisms, endogenous TME characteristics can be exploited. Tumors frequently have high concentrations of reducing agents like glutathione (GSH) and an acidic extracellular pH. In order to provide site-specific drug release without a requirement for external activation, magnetic nanocarriers can be designed with pH-sensitive and redox-responsive components that split or rearrange in response to these stimuli. In order to improve localized therapeutic activity, for instance, pH-responsive magnetic nanogels have been produced for the delivery of drugs to treat breast cancer. The drug is released from the magnetic carrier when the tumor microenvironment becomes acidic [85]. The hybrids systems are promising that enable multi-stimuli control over drug release by combining AMF responsiveness with pH or redox sensitivity. These advanced designs enable logic-gated release, which improves safety and effectiveness in varied tumor settings by releasing drugs only in response to certain combinations of internal and external stimuli [78, 86].

Fig. 2.

Iron oxide nanoparticles (γ-Fe2O3) in TLN can induce hyperthermia with externally applied AMF pulses, providing fine spatiotemporal control over thermoresponsive drug delivery. When injected into TLN, paclitaxel provided chemotherapy, whereas γ-Fe2O3 caused hyperthermia under AMF to stimulate drug release [83]

The hybrid magnetic nanocarriers achieve logic gated drug release through physicochemical interactions occurring at the magnetic core–shell interface, where the magnetic core acts as an energy transducer and the surrounding shell functions as a stimulus-responsive gate. When an AMF is applied, superparamagnetic iron oxide nanoparticles dissipate magnetic energy through Néel and Brownian relaxation mechanisms, generating localized nanoscale heat at the particle surface. Through creating structural changes in the shell material, such as polymer phase collapse, lipid membrane instability, or enhanced polymer chain mobility, this interfacial heating can improve shell permeability and facilitate the release of pharmaceuticals that are encapsulated [87, 88]. Moreover in multi stimuli systems, additional chemical responsive bonds are incorporated into the shell layer to exploit TME conditions. The redox-sensitive disulfide connections can be broken by high intracellular glutathione levels, but pH-sensitive bonds like hydrazone or acetal bonds are stable at physiological pH. These hydrazone or acetal hydrolyze in acidic tumor condition. In response to tumor-specific stimuli, this mechanism enables the shell matrix to undergo structural loosening or chemical decomposition. Combining these chemical triggers with AMF-induced magnetothermal activation which results in AND-gate logic behavior in magnetic nanocarriers. Here the drug release only happens when both external magnetic stimulation and tumor microenvironment conditions are present [89, 90]. Heat transfer efficiency and diffusion routes, which are greatly affected by polymer glass-transition temperature, shell thickness, and surface functional groups, are also significantly affected by the core-shell contact. The optimization of these parameters provides effective energy transfer from the magnetic core to the shell matrix, while maintain nanoparticle stability and regulated release kinetics. Consequently, rational engineering of the core–shell interface is essential for designing multi-stimuli magnetic nanocarriers capable of precise spatiotemporal drug delivery in breast cancer therapy [91].

Bio-magnetic nanomedicine in multimodal breast cancer therapy

In addition to enhancing targeted drug delivery, bio-magnetic nanomedicine provides a flexible platform that facilitates multimodal therapeutic synergism in breast cancer. Magnetic nanoparticles have several uses in targeted administration, imaging contrast, and treatment augmentation. It provides precisely regulated chemotherapeutic and heat-induced cytotoxicity with less systemic toxicity [13], . The synergistic effect of multimodal magnetic methods is demonstrated by studies using magnetic hyperthermia in breast cancer models, which show considerable improvement in chemotherapeutic effectiveness and tumor reduction when combined with traditional drugs [92]. Furthermore, magnetic approaches that combine field-triggered activation and controlled guiding have been suggested to improve specificity and address resistance to treatment for breast cancer [23]. Magnetic nanomedicine also enhances anticancer immune responses by combining thermal effects with immune activation, suggesting a possible approach for magneto-immunotherapeutic treatments [93]. Moreover, magnetic hyperthermia platforms increase treatment results beyond conventional chemotherapy by producing localized heat and influencing cellular stress responses [94].

Magnetically enhanced chemotherapy

Magnetically enhanced chemotherapy uses magnetic fields to increase cytotoxic exposure, enhances local drug accumulation at the tumor site, and combat multidrug resistance (MDR). MDR inhibits intracellular drug concentrations and therapeutic efficacy through a number of processes, including overexpression of efflux pumps such as P-glycoprotein (P-gp/ABCB1), altered drug metabolism, DNA repair, and apoptosis suppression. In addition to delivering insufficient drugs to tumor cells, conventional systemic chemotherapy frequently exposes healthy tissues to toxic doses, which contributes to treatment failure and emphasizes the need for advanced targeted delivery methods such magnetic carriers [95, 96]. In preclinical breast cancer models, enhanced local drug concentrations using magnetically guided nanoparticles have shown better tumor regression than free drug administration. It demonstrates the translational potential of magnetic targeting-induced localized dose amplification under an external magnetic field [97].

Magnetic hyperthermia synergism

Bio-magnetic treatment is magnetic hyperthermia (MHT) is another interesting approach which utilizes the advantage of super paramagnetic nanoparticles to produce heat under an AMF. Temperatures between 42 and 45 °C can cause sub-lethal stress in tumor cells, making them more susceptible to chemotherapeutic drugs and initiating apoptotic pathways that are normally resistant to standard therapies [23]. Magnetic hyperthermia can cause immunogenic cell death (ICD) that produces risk-associated molecular patterns (DAMPs) such calreticulin and HMGB1, in addition to chemosensitization. By stimulating anticancer immune responses and activating dendritic cells, ICD successfully transforms immunologically cold tumors into hot ones that respond better to immunotherapy. Studies demonstrated that localized hyperthermia from magnetic nanoparticle clusters boosted both innate and adaptive antitumor immunity when combined with chemotherapeutics [98]. As a result, magnetic hyperthermia not only increases the chemotherapy therapeutic window but also enhances antitumor immunity, offering new possibilities for combination with immunotherapeutic approaches.

Magneto-immunotherapy

Cancer immunotherapy has reshaped the landscape of oncology by harnessing the immune system to recognize and destroy tumor cells. However, breast cancers, especially aggressive subtypes like TNBC which often create immunosuppressive microenvironments that limit immunotherapy efficacy. Magneto-immunotherapy integrates magnetic targeting with immune modulation to overcome these barriers by directing immune effectors and modulatory agents precisely to the tumor region [99]. For example magnetic targeting of immune modulators such as cytokines, adjuvants, or immune checkpoint inhibitors using functionalized magnetic nanoparticles has been shown to enhance T cell infiltration and antitumor immunity in preclinical breast cancer models, as demonstrated by magnetic enrichment of anti‑PD‑L1 and T‑cell activating agents that increased intratumoral CD8⁺ and CD4⁺ T cells under an applied magnetic field, leading to improved therapeutic efficacy in a triple‑negative breast cancer xenograft model [93]. This strategy not only increases treatment precision but can reduce systemic immune toxicity often observed with high doses of immunotherapeutics.

Another magneto‑immunotherapy strategy focuses on tumor‑localized immune reprogramming by delivering immune‑stimulating agents directly into immunosuppressive niches within the tumor microenvironment. Iron-oxide-based magnetic nanoparticles, including polyaniline-coated systems, have been shown to reprogram tumor-associated macrophages (TAMs) from the immunosuppressive M2 phenotype toward the pro-inflammatory antitumor M1 phenotype through nanoparticle-induced redox signaling and activation of innate immune pathways within the tumor microenvironment (TME) [100]. In addition, multifunctional magnetic nanocarriers have been developed to co-deliver antigens and adjuvants to tumor-draining lymph nodes under magnetic guidance, enhancing vaccine-like antitumor immunity. Targeted delivery results in potent activation of dendritic cells and expansion of tumor-specific cytotoxic T lymphocytes, which can control both primary tumors and micrometastatic disease [101]. Table 4 shows comparative study green-synthesized magnetic nanomaterials for anticancer activities relevant to breast cancer with different approaches.

Table 4.

Comparative study of green-synthesized magnetic nanomaterials for breast cancer with different approaches

Green MNP / composite	Green source / extract	Therapeutic approach	Breast cancer application	Target cell/effect	References
Fe₃O₄ @ carboxymethyl chitosan loaded with curcumin	Carboxymethyl chitosan and Curcumin	Chemotherapy, Hyperthermia	MCF-7 combined treatment	Induces apoptosis, enhanced efficacy	[104]
Mg-Co ferrite NPs	Curcuma longa (turmeric) extract	Chemotherapy candidate	MCF-7 cells	Dose-dependent cytotoxicity & ROS	[38]
IONPs	Seaweed aqueous extract	Chemotherapy	MCF-7 cells	Inhibits proliferation (MCF-7)	[105]
IONPs /Ag composite NPs	Moringa oleifera extract	Hyperthermia potential	Magnetic hyperthermia focus	Temperature rise efficacy	[106]
IONPs	Green route (plant extract)	Chemotherapy candidate	Cytotoxic evaluation	Potential anticancer application	[107]
IONPs	Grape seed extract	Chemotherapy candidate	General anticancer exploration	Potential cytotoxic	[108]

Iron oxide based magnetic nanoparticles can actively modulate macrophage phenotype by multiple physicochemical interactions with the TME. Following cellular uptake through endocytosis or scavenger receptor mediated pathways. These nanoparticles accumulate within endolysosomal compartments where gradual degradation releases Fe²⁺ and Fe³⁺ ions. The intracellular iron pool can trigger Fenton-type reactions that generate reactive oxygen species (ROS), which subsequently activate pro-inflammatory transcription factors such as nuclear factor-κB and interferon regulatory factor-5. Activation of these pathways promotes the expression of M1-associated genes including inducible nitric oxide synthase, interleukin-12, and tumor necrosis factor-α, while suppressing M2 markers such as arginase-1. Similarly, iron-mediated oxidative signaling and Toll-like receptor activation stimulate mitogen-activated protein kinase pathways, further enhancing inflammatory cytokine secretion and macrophage reprogramming toward an antitumor M1 phenotype. Surface engineering of iron oxide nanoparticles, including conductive polymer coatings such as polyaniline, can further improve macrophage interaction, cellular uptake, and intracellular redox modulation, thereby amplifying immunostimulatory signaling within the tumor microenvironment and promoting tumoricidal immune responses [100, 102, 103].

Nano-bio-magnetic interface in breast cancer

Recent studies have demonstrated that magnetic forces applied through nanoparticles can mechanically modulate the tumor microenvironment by influencing cytoskeletal organization and stiffness, as evidenced by actin‑targeted magnetic nanomotors that alter breast tumor mechanics and suppress growth under external magnetic fields [109]. In addition, the intracellular mechanical microenvironment of breast cancer cells was found to critically influence magnetic nanoparticle behavior during hyperthermia, underscoring the role of mechanobiological properties in magnetic therapeutic responses [110]. The mechanistic studies reveal that when low-frequency magnetic fields are applied to internalized magnetic particles, have the capability of disrupting cellular function [111]. In addition magnetically induced mechanosensing has demonstrated the capability of magnetic forces in altering the structure of the cytoskeleton by the biological system [112]. MNPs have the capability of converting the applied magnetic field into localized forces that act on cellular and membrane-associated structures. This is the major insight into magneto-mechanobiological interactions. MNPs have the capability of applying torque and translation forces when exposed to low-frequency alternating magnetic fields. This capability has the ability to disrupt the structure of the cytoskeleton. As demonstrated by earlier studies, MNPs have the ability of disrupting microtubules and actin filaments, resulting in disorganization of the cytoskeleton, leading to cancer cell death [111]. On the other hand magnetic hypothermia, and the magneto-mechanical simulation method both utilize magnetic nanoparticles. The difference in the magnetic fields used in the two methods is considerable. The magnetic fields used in the magnetic hyperthermia method generally work at high-frequency alternating magnetic fields of 100 to 500 kHz, along with a magnetic field amplitude of 10 to 30 kA m⁻¹. This is to enhance the energy dissipation through the Néel and Brownian relaxation mechanisms to enhance the localized temperature of the tissue [87, 113, 87, 114]. This results in a temperature of 42 to 45 °C, leading to cancer cell death and the enhanced release of drugs from the nanoparticles.

However, low-frequency magnetic fields (usually below 100 Hz) or oscillating magnetic gradients are typically used for cytoskeletal disruption or magneto-mechanical therapy. These magnetic fields exert mechanical torque and translational forces on internalized magnetic particles rather than producing appreciable thermal effects. Actin filaments, microtubules, and membrane-associated proteins are examples of intracellular structures that these stresses can physically disrupt, leading to cytoskeletal instability and modified mechanotransduction signaling. Thus, there are two different physical processes of magnetic nanoparticle activation in cancer therapy. Magneto-mechanical techniques function through force-mediated cellular disruption, whereas hyperthermia mainly depends on thermal energy conversion [91]. This mechanical stress is especially relevant in cancer cells, as their cytoskeletal architecture is weaker than non-malignant cells, increasing their susceptibility to force-induced damage [115]. Magnetic field and MNPs can affect fluidity of membranes and endosomal transport in addition to cytoskeletal effects. When intracellular MNPs are subjected to external magnetic gradients, endosomal membranes may experience mechanical forces that impact their stability and trafficking pathways. Long-term magnetic stimulation can damage the endosomal membrane and increase MNP interaction with early endosomes. It improve early release of drug and facilitates the release of therapeutic medicines into the cytoplasm [114]. These results suggested that in addition to drug delivery, magnetic field can also affect the intracellular tracking paths.

Mitochondrial stress is also based on magnetomechanical interactions. Targeting mitochondria, magnetic nano-transducers transform external magnetic force into mechanical stress, affecting the function of mitochondria and causing cancer cells to undergo apoptosis and mitophagy [116]. Mitochondrial disruption not only activates intrinsic apoptotic pathways, but it also has an impact on metabolic reprogramming, ROS production, and cellular redox balance parameters, all of which are frequently abnormal in cancer. Breast cancer has a high intratumoral heterogeneity, with subpopulations of cancer stem cells (CSCs) contributing to resistance, recurrence, and metastasis. Mechanobiological stimuli have a significant impact on CSC activity, since mechanical pressures and extracellular stiffness alter stemness and differentiation. Although specific studies on the impact of magnetic fields on cancer stem cells are scarce, larger mechanobiology research indicates that physical forces influence CSC destiny and mechanotransductive signaling pathways that coordinate self-renewal and therapeutic resistance [117]. Integrating MNP-mediated mechanostimulation with CSC targeting strategies might give novel ways to eliminate resistant cell groups. Furthermore, the magneto mechanotransduction approach allows for the specific control of cellular processes through physical means, whereas emerging evidence suggests that mechanically generated forces could have unexpected biological consequences. The magnetic force applied to the cell membrane or cellular compartments activates mechanosensitive signal transduction pathways such as the integrin/β-catenin pathway. It has been associated with epithelial-to-mesenchymal transition (EMT) and motility in non-specific contexts. Experimental models using magnetic force to modulate MNP-containing cells have reported alterations in cellular structures, which have been associated with the mechanisms regulating EMT [118].

Epithelial mesenchymal transition (EMT) is also sensitive to mechanical cues. Matrix stiffness, shear stress, and cytoskeletal tension are known to regulate EMT-associated transcription factors such as Snail, Twist, and ZEB1. While direct evidence of magnetic field induced EMT modulation is still emerging, the interplay between mechanical force and EMT is well documented in the mechanobiology field, and magnetic manipulation of intracellular forces presents a promising modality to disrupt EMT progression and metastatic phenotypes [119]. Mechannotransduction transduction the conversion of physical stimuli into biochemical signals is an essential aspect of mechanobiology in breast cancer. Integrated molecules and focal adhesion complexes detect mechanical signals such as stiffness and cytoskeletal tension, triggering the focal adhesion kinase (FAK) and RhoA/ROCK pathways, which govern cell shape, migration, and mechanosensing responses in breast cancer cells. Mechanosensitive ion channels translate membrane stress into signaling cues, influencing proliferation and invasion in the TME [120–123]. Magneto-mechanobiology affects interactions with the TME, in addition to single cells. Forces transmitted through extracellular matrices and cell-cell interactions can change stiffness gradients, interstitial pressures, and cellular architecture, influencing immune cell infiltration and stromal cell activity in breast cancer. Physical indicators such as matrix stiffness and mechanical stress have been demonstrated to promote malignant growth and influence immunological responses inside the TME, emphasizing the relevance of mechanobiological interactions at the tissue level [124].

Imaging-guided bio-magnetic drug delivery

The combination of imaging modalities and therapeutic activities is an essential part of bio-magnetic nanomedicine, allowing for real-time tracking, accurate localization, and evaluation of drug delivery success in breast cancer therapy. Imaging-guided drug delivery (theranostics) combines diagnostic imaging and therapeutic intervention, allowing clinicians to noninvasively observe nanocarrier distribution, track drug release kinetics, and dynamically adjust therapies [13]. MRI, magnetic particle imaging (MPI), and hybrid dual-modal systems (e.g., MRI-fluorescence, MRI-photoacoustic) are essential imaging methods because of their complementing capabilities in spatial resolution, deep-tissue penetration, and signal specificity [125].

MRI-guided real-time tracking

MRI is one of the most applied clinical imaging modalities used to diagnose cancer and guide nanomedicine therapies. It provides great spatial resolution, outstanding soft tissue contrast, and the ability to observe anatomical features in three dimensions without using ionizing radiation. MIONPs act as effective MRI contrast agents by reducing the transverse relaxation time (T2) of water protons in tissues, resulting in negative contrast enhancement in T2-weighted images [126]. Figure 3 shows the synthesis and workflow of the superparamagnetic iron oxide nanoparticles imaging probe (SPIOs@A-T NPs) to detect metastatic lymph node (MLN) of breast cancer by using dual-modality fluorescence molecular imaging (FMI) and MPI [125].

Fig. 3.

A schematic representation of the synthesis and processing of SPIOs@A-T NPs to detect MLN in breast cancer employing dual-modality FMI and MPI to actualize a strategy for the specific and sensitive detection of MLN. Lymph node; LN, Metastatic lymph node; MLN, Normal lymph node; NLN, Fluorescence molecular imaging; FMI, and Magnetic particle imaging; MPI [125]

In the context of breast cancer medication delivery, MRI could be utilized to monitor the biodistribution of magnetic nanocarriers, validate accumulation in tumor tissues, and measure treatment response over time. Beyond the traditional difference, there is rising interest in activatable dual-mode MRI probes that enable enhanced specificity. pH-responsive nanoparticles with core-shell designs, as SPIO@SiO₂@MnO₂, improve sensitivity and differentiate between malignant and normal tissues in acidic tumor environments [127]. Such environment-responsive MRI contrasts with chemicals improve in the early diagnosis and precise mapping of tumor margins, which is essential for precision treatment. MRI guiding also enables real-time monitoring of complicated delivery systems. For example, biodegradable capsules or magnetic nanocarriers intended to release chemotherapeutic drugs may be tracked throughout their transit and retention in breast tumor tissues, allowing clinicians to adjust the doses based on in vivo feedback [128].

Magnetic particle imaging (MPI)

MPI is a new imaging technique that detects the nonlinear magnetization response of magnetic nanoparticles with great sensitivity and little background signal from surrounding tissues. Unlike MRI, MPI generates contrast only from the tracers, resulting in quantitative pictures free of tissue signal interference [129]. Because of this characteristic, MPI is especially useful for tracking the temporal and spatial distribution of magnetic nanocarriers employing deep-tissue visualization and considerable contrast. MPI zero-background imaging provide a precise detection of tracer accumulation in tumors and metastatic which enables real-time evaluation of the effectiveness of drug administration. Due to improvements in tracer design and hardware platforms, now MPI can track therapeutic nanocarriers in preclinical cancer models. New trend is the synthesis of specific MIONPs tracers appropriate for MPI, which enhance signal quality while identifying low nanoparticle concentrations in vivo [130].

Dual -modal systems (MRI–fluorescence, MRI–PA)

Combining technologies allows for better monitoring by addressing the limitations of individual imaging techniques. By combining two complimentary methods, dual-modal imaging offers both anatomical context and molecular or functional information. For instance, great spatial resolution and sensitive molecular marker identification are made possible by combining MRI with fluorescent imaging (FLI). Dual-modal probes that permit simultaneous MRI monitoring and optical tracking of nanocarrier distribution are made possible by coating magnetic nanoparticles with fluorescent sensors [131]. Similarly, combining MRI with photoacoustic (PA) imaging improves contrast and functional characterisation. PA imaging offers high-resolution observation of tissue oxygenation and vascular architecture by identifying ultrasonic waves produced by pulsed laser stimulation of absorbers. Integration of PA contrast agents with magnetic carriers made possible a comprehensive evaluation of the therapeutic impact of nanomedicine distribution. It enables simultaneous tracking of the anatomical location (by MRI) and biological function (via PA) [132]. Especially in breast cancer, these multimodal imaging techniques are important, where single-mode imaging is usually limited by different tissue composition and the complexity of the TME. Dual-modal approaches provide dynamic evaluation of therapeutic results, which improve detection accuracy, and allow cross-validation of signal sources [133].

AI-assisted closed-loop magnetic navigation systems

In magnetic drug delivery systems, artificial intelligence (AI) and machine learning are rapidly integrated with imaging-guided nanomedicine to enable closed loop control. AI systems can enhance tissue-specific navigation, adjust magnetic field settings, and predict nanocarrier dispersion by analyzing imaging data. For example, AI-assisted frameworks have been established to enhance real-time data from MRI or MPI, enabling autonomous change of magnetic guidance to optimize nanocarrier accumulation within tumor sites [134]. By understanding the temporal and spatial characteristics of nanoparticle mobility, AI models may improve magnetic field navigation, take physiological variability consideration, and reduce operational dependence. Additionally, MPI’s image reconstruction sensitivity and resolution have been enhanced by deep learning approaches, providing more precise input for magnetic navigation control [129]. Primary objective of these closed loop devices is to provide a flexible therapeutic environment where imaging continuously controls targeted distribution to enable customized and better therapies is the. AI-assisted magnetic navigation has huge potential to increase the accuracy and effectiveness of bio-magnetic nanomedicine for breast cancer [135].

Toxicological, biodegradation, and biosafety considerations

Biosafety, biodegradation, and toxicological profiles should be carefully evaluated for successful translation of bio-magnetic nanomedicine for targeted breast cancer therapy. Despite the therapeutic potential of MNPs, issues regarding cytotoxicity, long-term effects, and disruptions to iron metabolism are highlighted by their complicated interactions with biological systems. Additionally, safety profiles can be greatly affected by synthesis processes, especially the differences between conventional and green chemical operations [13]. This section covers the major factors affecting the biocompatibility and clinical viability of magnetic nanocarriers.

Long term fate of magnetic nanoparticles

Monitoring the long-term biodistribution and clearance MNPs is necessary for evaluating their safety. After application, the reticuloendothelial system (RES) enables MNPs to enter important organs such the spleen, liver, and lungs. Macrophages and other phagocytic cells often ingest these particles, where they can remain for an extended period. According to reported studies, surface coating, particle size, and agglomeration are the primary factors which affect the degradation and clearance of iron oxide nanoparticle (IONP). Clearance pathways are more efficient for the smaller and better-coated particles [136]. Particularly, the accumulation of MNP in the spleen and liver may persist even after therapy and, if left unchecked, may cause long-term inflammatory reactions. Phagocytes biodegrade iron oxide cores through lysosomal processing, releasing iron ions that are either bound by transport proteins like ferritin and transferrin or incorporated into endogenous stored iron. When released iron is absorbed into normal iron metabolism pathways following macrophage absorption and lysosomal breakdown, the expression of ferritin and transferrin (iron-associated proteins) increases [137]. These findings highlight the importance of closely monitoring iron homeostasis for a long time after MNP therapy.

Iron homeostasis disruption risks

The degradation products MIONPs (especially iron ions) can disrupt systemic iron homeostasis if released in excess. While iron is essential for DNA synthesis, oxidative metabolism, and oxygen transport. So, its deregulation can generate reactive oxygen species (ROS) via Fenton reactions. Recent studies evaluating the safety of iron oxide nanoparticles indicate that, if the body’s sequestration capacity is exceeded, a prolonged increase in labile iron pools may promote oxidative stress, lipid peroxidation, and DNA damage in non-target tissues [138]. Small amount of released iron can be handled by physiological homeostatic mechanisms; however, prolonged or excessive iron release may lead to adverse effects, such as hepatic injury and cardiovascular stress, particularly in the case of weakly biodegradable MNPs [138]. Moreover, iron overload has been associated in certain contexts with tumor initiation and metastasis through alterations in immune cell function and oxidative signaling pathways. Therefore, strict control over nanoparticle degradation kinetics, along with monitoring of systemic iron biomarkers (e.g., serum ferritin and transferrin saturation), is essential to minimize unexpected outcome [139–141].

Ferroptosis and oxidative toxicity

When MNPs interact with cellular oxidative processes, there are two possible effects. Ferroptosis (which is controlled, iron-dependent kind of cell death characterized by lipid peroxidation and glutathione depletion) can be used therapeutically to eradicate cancer cells only. Ferroptosis generated by iron-based nanomaterials has become a potential anticancer approach, especially for phenotypes resistant to treatment, such as triple-negative breast cancer (TNBC) [142]. These nanoplatforms promote ROS production beyond the cellular antioxidant capacity by causing catalytic iron release into cancer cells, which eventually results in tumor cell death. However, non-specific oxidative damage can result from excessive or uncontrolled ROS production, negatively impacting healthy tissues. Increased ROS levels can cause necrosis and inflammatory reactions by damaging DNA, compromising cellular membranes, and disturbing mitochondrial function. Consequently, it is crucial to differentiate between therapeutically favorable ROS levels and toxic oxidative stress. While controlled ferroptotic induction necessitates exact adjustment of nanoparticle composition and drug carriers, unexpected oxidative damage highlights the significance of adequate cytotoxicity profiling in tumor and normal cells [143].

Ferroptosis driven by magnetic nanoparticles has quickly become a highly promising oncotherapeutic approach for breast cancer, especially in triple-negative subtypes where traditional therapies are ineffective. Recent research has shown that by raising intracellular labile iron pools and lipid peroxidation, magnetic nanostructures can dramatically increase ferroptotic cell death. Wei et al. created a lysosome-targeted magnetic nanotorquer (T7-MNT) that, when exposed to a rotating magnetic field, mechanically disrupts lysosomes, releases endogenous Fe(II), and encourages ferroptosis in models of breast cancer. This method illustrated the possibility of magneto-mechanical ferroptosis induction and showed improved tumor regression in vivo [144]. Magneto-photo-acoustic nanotheranostics are complementary phases that provide synergistic tumor reduction and metastasis suppression by amplifying ferroptosis and immune activation in triple-negative breast cancer in addition to guiding tumor targeting through imaging [145].

Safety comparison of green and chemically synthesized systems

The synthesis technique has a significant impact on the safety and biocompatibility of MNPs. High temperatures, organic solvents, and toxic reducing agents are frequently used in conventional chemical synthesis, which can result in persistent pollutants or unstable surface chemistries that can cause harmful biological interactions. Green synthesis methods, on the other hand, create biocompatible surface capping layers and nanoparticles in mild aqueous conditions. These biomolecule-derived coatings, which are often made of proteins, polysaccharides, and flavonoids, improve colloidal stability, reduce the development of protein corona, and encourage positive immunological interactions [34]. Additionally, different synthesis techniques provide unique biodegradation characteristics to MNPs. The risk of bioaccumulation may be increased by chemically manufactured MNPs with thick synthetic coatings that may resist degradation and persist in tissues for long periods of time. Green synthesis methods, on the other hand, frequently result in nanoparticles with loosely attached organic coronas which assist in enzymatic break down [146].

Regulatory issues for magnetic nanoparticles drug combination products

Regulatory authorities such as U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require rigorous evidence of safety, efficacy, and quality for any medicinal product, but nanomedicines do not fit neatly into existing frameworks designed for conventional drugs or medical devices. Nanoparticles frequently exhibit unique pharmacokinetics, biodistribution, and physico‑chemical properties that differ markedly from their bulk counterparts, complicating standard evaluations of safety and efficacy [147, 148]. However, the regulatory definition of combination product encompasses of FDA products that combine drugs, devices, and/or biologics in a single entity or in co‑packaged form. According to the agency, such products require coordination between multiple review centers and may require early regulatory consultation through mechanisms like Requests for Designation (RFDs) and pre RFDs.

There is no specific regulatory framework for nanomedicines in Europe. They are governed by the laws currently in place for medical products. The latest EMA study on nanotechnology-based medical goods emphasizes that while nanomedicines are governed by traditional medicinal product regulations, regulatory submissions face difficulties due to the lack of a uniform legal framework and harmonized terminology. To lower the categorization ambiguities, developers frequently need to obtain early scientific advice through organizations like the Scientific Advice Working Party and Innovation Task Force [149].The main challenges are; (a) Depending on its main mode of action and intended usage, nanomedicine products may be regulated as medicines, devices, or drug-device combinations. This uncertainty may result in different submission procedures and regulatory processes across nations, raising the risk and expense of development [149, 150]. (b) Critical quality characteristics of nanoparticle systems, such as particle size distribution, surface chemistry, and in vitro release kinetics, are not well captured by conventional analytical and production standards. Significant gaps in standardized characterisation techniques have been found by both manufacturers and regulators, reducing the predictability of regulatory assessments [148]. (c) Regulatory review is slowed by the lack of standardized test batteries for nanomedicines, which frequently require extra physico-chemical and biological characterisation beyond usual criteria (e.g., stability, immunogenicity, biodistribution) [147]. (d) Sponsors of combination products must coordinate overlapping standards (such as CGMP requirements under 21 CFR Part 4), interact with various regulatory units (such as the FDA’s Office of Combination Products), and meet both drug and device regulatory requirements, all of which can prolong development timelines. (e) It is difficult to achieve GMP standards needed for human clinical research and market approval due to variations in synthesis, batch variability, and scale-up inconsistency [147].

Despite encouraging preclinical findings, few magnetic nanoparticle medicine nanoformulations go past the early stages of clinical trials, which can be partially explained by these regulatory obstacles. Long-term safety issues, uncertainty around immune recognition and biodistribution, and a lack of regulatory agency harmonization are all factors that contribute to these restrictions [151].

Translational and clinical challenges

Interdisciplinary challenges still impede the translation of bio-magnetic nanomedicine for targeted drug delivery in breast cancer from laboratory success to clinical efficiency. These include the physical limitations of applying magnetic fields to patients, the manufacturing and commercialization of green-synthesized devices, and complex ethical and regulatory frameworks. Beyond technology innovation, the bridging of these translational gaps, integrated approaches for patient safety, regulatory alignment, and systematic evaluation are important [152].

Magnetic field application in patients

The primary translational issues are the practical implementation of magnetic field guided drug delivery in clinical settings. As magnetic targeting has improved nanoparticle retention in tumors in animal models, but there are severe anatomical and physical barriers to its use in human patients [22]. The intensity and gradient of the applied magnetic field, which quickly reduce with increasing distance from the magnet, are the major factors in magnetic drug targeting. As successful targeting with external magnets is limited to surface malignancies, therefore deep-tissue targeting therapy is unfeasible. According to experimental and theoretical research, the magnetic carriers usually effective guided within a few centimeters of the body surface and the rapid decrease of the magnetic field makes efficient targeting at deeper depths is still unsolved challenge [153]. Although breast tumors are often more superficially placed than many other malignancies, however the variations in lesion depth and patient body position can have a major impact on the capacity of magnetic fields to regulate nanoparticle dispersion with therapeutic precision. Furthermore, the strength and gradient of external magnetic fields needed to guide nanoparticles into deeper tissues may produce safety issues. Because higher field strengths may cause tissue heating or unintentionally stimulate excitable tissues like muscles and nerves, so they need careful technical and clinical validation. Recent developments in magnet design that aim to increase effective penetration depth while preserving patient safety include focused electromagnetic coils and optimized magnetic arrays. However, these technologies are still mostly in the experimental stage and have not yet been incorporated into standard clinical procedures [153, 154]. These anatomical variances demand particular magnetic field optimization and imaging-guided delivery strategy to achieve consistent targeting efficacy across several patient populations. The integration of patient-specific imaging data with magnetic field models and treatment planning tools has the potential to increase targeting precision, but such techniques are still being investigated [155]. Figure 4 shows the schematic illustration of major barriers to clinical translation in bio-magnetic nanomedicine for targeted breast cancer therapy.

Fig. 4.

Translational and clinical challenges in bio-magnetic nanomedicine for targeted breast cancer therapy

Manufacturing and scale-up of green-synthesized systems

Green synthesis of MNPs has numerous advantages in terms of biocompatibility and environmental sustainability. It also has many synthesis and scale-up problems when moving from bench to good manufacturing practice (GMP) grade production [156]. Plant extracts, microbial activities, or biomolecules are often used in green synthesis to decrease metal precursors and cap nanoparticles under moderate aqueous conditions. Although such approaches can produce particles with naturally biocompatible surfaces and low toxicity, they typically exhibit batch-to-batch variability due to the complexity and variety of biological reducing and capping agents [157].

For the successful translation of green synthesized MNPs into clinical applications, it is essential to meet Good Manufacturing Practice (GMP) requirements by incorporating robust analytical assays that ensure reproducibility and biological performance across production batches. The major characterization essays are; (a) Physical profiling of size, morphology, and polydispersity using high‑resolution transmission electron microscopy, dynamic light scattering, and nanoparticle tracking analysis to verify consistent particle morphology and surface coating across batches. (b) Quantitative surface chemistry assays, including Fourier‑transform infrared spectroscopy and X‑ray photoelectron spectroscopy, to confirm consistency in functional ligand density and biomolecular corona composition. (c) Biomolecular corona profiling, such as proteomic mass spectrometry after incubation in defined human plasma, to characterize the protein composition adsorbed onto the nanoparticle surface and ensure predictable biological identity. (d) magnetic characterization (e.g., vibrating sample magnetometry, SQUID magnetometry) to confirm uniform magnetic response essential for targeting under external fields. (e) In vitro functional assays, including cellular uptake quantification and immune activation screens, to ensure consistent biological behavior. The standardization of these analytical endpoints under GMP conditions will minimize batch‑to‑batch variability and improve regulatory compliance in nanomedicine translation [158].

Variations in particle size distributions, magnetic characteristics, and surface chemistries might arise from seasonal, regional, or processing variations in plant extract content, which can have a significant impact on medicinal efficacy and safety. Clinical translation requires the establishment of standardized green synthesis processes with high standards of quality. The repeatability of MNPs is required to optimize biological extract preparation, reaction conditions, and downstream purification. Because they have a main influence on pharmacokinetics and immunological interactions in biological systems, particle size, biomolecule identification, magnetization, and surface coverage must all be incorporated in analytical characterization [159]. There are additional problems when using green synthesis techniques on an industrial scale while under GMP regulations. Complex organic chemical combinations may be introduced via biological synthesis methods, requiring extensive purification to satisfy regulatory requirements for excipients and contaminants. Usually complexity in chemical synthesis is not considered to ensure sterility, endotoxin absence, and stability under storage conditions the complexity is not [160]. Due to their complex physicochemical profiles and manufacturing dependencies, the regulatory agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require comprehensive records of process controls, raw material, and contamination risk management for nanomedicines [161, 162]. This documentation is important for green synthetic systems to establish new frameworks which achieve an acceptable balance between the intrinsic variability of biological materials and the stringent standards of pharmaceutical manufacture. The current standards, which are still in initial stage, emphasize the need for defined quality characteristics and evaluation criteria to ensure efficacy and safety [163].

Regulatory and ethical considerations

Due to the complexity of these technologies, which include drugs, devices, and even biologics, the clinical translation of bio-magnetic nanomedicine also faces ethical and regulatory challenges. The absence of internationally consistent regulations makes it difficult to conduct comprehensive risk-benefit evaluations and clearance processes, and nanomedicines often lack a defined regulatory framework. The failure of regulatory bodies to adapt traditional effectiveness and safety evaluation models to account for nanoscale properties impedes the clinical acceptance of innovative nano-therapeutics. In addition to making manufacturing compliance more difficult, this disconnected regulatory environment raises ethical questions about patient protection and safety assessment in new nanomedical drugs compared to more traditional breast cancer treatments [164]. A therapeutic drug, a nanomaterial, and an external magnetic field sensor for targeting or imaging guiding are frequently combined in magnetic nanocarrier systems. The regulatory clearance procedures for combination products are more complex compared to single drugs or devices [165]. Regulators typically demand comprehensive data from pharmacokinetic, pharmacodynamic, biodistribution, and toxicology studies tailored to nanoparticle systems, incorporating both the nanomaterial and the mode of magnetic field application. Additionally, safety requirements for electrical and thermal qualities in human usage must be satisfied by device components (such magnetic field generators). Development delays and expenses can be greatly increased by navigating these multi-component approval procedures [166]. Another ethical and safety concern is the effects of repeated exposure to magnetic fields in patients. Therapeutic magnetic targeting may need longer or higher field gradients, however static magnetic fields used in clinical MRI are often regarded as safe at diagnostic intensities [167].

Emerging trends and future perspectives

Recent advances in magnetically guided drug delivery, such as the invention of magnetically driven bionic nanorobots that enhance chemotherapeutic targeting and antitumor immune responses in preclinical models, show the potential of active magnetic navigation systems in cancer [168]. In order to improve drug delivery and penetration in tumor tissues, including aggressive subtypes like triple-negative breast cancer (TNBC), recent studies describe the design of self-propelling magnetic nanobots that take advantage of the catalytic breakdown of endogenous hydrogen peroxide for autonomous motion. These systems were shown to internalize more efficiently into TNBC cells, reducing IC₅₀ values compared to free drug treatment, and promoting intracellular ROS production that contributes to cytotoxicity and enhanced therapeutic outcoms [169]. Magnetically driven bionic nanorobots that combine improved magnetic responsiveness with preprogrammed movement patterns reinforce these self-propelling designs. When compared to free chemotherapeutic controls, these magnetically directed nanorobots demonstrated over ten-fold increased accumulation at tumor sites, sustained drug release, activation of localized immune responses, and longer life in tumor-bearing mice models [168]. Developments highlighted the potential of nanorobots to enhance drug distribution and penetration as well as to work in collaboration with immune systems to provide more powerful cancer treatment. Despite these promising preclinical results, there are still challenges to be addressed before nanorobots may be applied in clinical settings. These include ensuring biocompatibility, avoiding rapid clearance by the immune system, optimizing propulsion mechanisms within physiological fluids, and integrating real-time imaging and control systems. Continued research into materials engineering, field actuation strategies, and safety assessment will be crucial for clinical adaptation [170].

Magnetically driven, exosome-mediated nanocarriers that combine ferroptosis inducers with superparamagnetic nanoparticles have demonstrated notable tumor targeting and therapeutic benefits in breast cancer models [171]. Because of their intrinsic biocompatibility, potential to cross biological barriers, and intrinsic cargo-carrying capabilities, exosomes have attracted significant interest as next-generation drug delivery vehicles. Exosome-based drug delivery is of particular interest for cancer therapy because of its benefits, which include effective transfer of therapeutic drugs and low immunogenicity when compared to synthetic carriers [172]. A developing area of targeted breast cancer treatment is the use of magnetic components into exosome platforms. Recent studies reported the exosome-mediated and magnetic nanoparticle-driven nanovesicles intended for dual targeting and ferroptosis activation in migratory breast cancer cells. These complex mechanisms provide both magnetic guiding and increased ferroptotic cell death by combining functional exosomes with superparamagnetic nanoparticles and therapeutic drugs like sorafenib [171]. The benefits of biological vesicles for tumor targeting are utilized by these hybrid exosome-magnetic structures, which also allow for accurate localization and regulated therapeutic release by external field modulation. Despite its potential, the practical translation of exosome-based magnetic systems is still challenging due large scale synthesis of exosome, effective drug loading, optimization of delivery techniques, and focused magnetic control [173].

A new therapeutic approach to enable image-guided therapy and locally trigger iron-dependent cell death is ferroptosis-inducing magnetic nanoparticles [174]. There is great interest in investigation of ferroptosis application for treating therapy-resistant cancers, such as aggressive breast cancer. Research on ferroptosis cancer nanomedicine mediated by MNPs emphasizes the dual role of magnetic carriers in delivering iron ions and simultaneously facilitating image-guided treatment via MRI, resulting in synergistic therapeutic and diagnostic benefits [175]. Ferroptosis-centered designs seek to overcome resistance mechanisms that exist in apoptosis-based treatments by using the catalytic activity of magnetic nanoparticles to raise intratumoral iron levels and produce ROS by using Fenton chemistry. By selectively releasing iron in the oxidative and acidic tumor microenvironment, these nanoplatforms can improve localized cell death with few off-target effects. However, integration with imaging capabilities provides more opportunities for real-time tracking of therapy engagement and progression [176].

Finally, patient-derived organoid models circulating tumor cell-derived models, and patient-derived xenografts provide specific evaluation of latest magnetic nanomedicine techniques for the best possible treatment by retaining tumor heterogeneity and microenvironmental context [177, 178]. In the context of magnetic nanomedicine, these models enable patient-specific predictive assessment of targeted therapeutics, magnetic targeting effectiveness, ligand specificity, and resistance mechanisms. As these tumor organoids maintain the heterogeneity and microenvironmental interactions of original tumors, so they are widely used for screening nanomedicine and testing drug sensitivity [179]. A precision oncology approach is made possible by combining patient-derived tumor platforms with magnetic drug delivery devices. This makes it possible to optimize therapeutic protocols, nanoparticle designs, and magnetic targeting settings based on individual response profiles before clinical administration. Moreover, advances in organoid technology, like as chip-based organoid systems (that replicate intricate tumor microenvironments and circulatory dynamics) will provide even more precise models for preclinical evaluation [180].

Conclusion

Bio-magnetic nanomedicine changes passive drug delivery by precision-guided therapeutic navigation system in breast cancer. This review demonstrates how green synthesis techniques give magnetic nanoparticles better biocompatibility, modified magnetic relaxation behavior, and enhanced nano–bio interactions, all of which improve therapeutic and theranostic performance in addition to addressing issues related to sustainability. The potential of magnetic control to overcome tumor heterogeneity, multidrug resistance, and off-target toxicity is highlighted by advances in functional design such as dual-targeting ligands, magneto-responsive AND-gate drug release, and core–shell designs. Furthermore, new ideas such as magneto-immunotherapy, magneto-mechanobiology, and imaging-guided closed-loop systems extend the function of magnetic fields from active biological modulators to guidance devices. Despite these developments many translational challenges still exist, especially in long-term biosafety, scalable green manufacturing, magnetic field application in patients, and regulatory procedure for drug-device combination therapies. Standardized evaluation frameworks and close cooperation between materials scientists, oncologists, engineers, and regulators will be necessary to address these issues. Moreover, bio-magnetic nanomedicine establishes a possible link between nanotechnology and specific breast cancer treatment, providing an appropriate way toward clinically feasible, precisely regulated therapeutic approaches.

Author contributions

YF and YZ designed the review, collected the literature and wrote the draft. HZ and TM organized and analyzed the literature. HW supervised, conceptualized and revised the review.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.