coatings

Review
Recent Advances in Surface Functionalization of
Magnetic Nanoparticles
Cezar Comanescu 1,2

1 National Institute of Materials Physics, Atomistilor 405A, 077125 Magurele, Romania;

[Link]@[Link]
2 Faculty of Physics, University of Bucharest, 405 Atomistilor St., 077125 Magurele, Romania

Abstract: In recent years, significant progress has been made in the surface functionalization of mag-
netic nanoparticles (MNPs), revolutionizing their utility in multimodal imaging, drug delivery, and
catalysis. This progression, spanning over the last decade, has unfolded in discernible phases, each
marked by distinct advancements and paradigm shifts. In the nascent stage, emphasis was placed
on foundational techniques, such as ligand exchange and organic coatings, establishing the ground-
work for subsequent innovations. This review navigates through the cutting-edge developments
in tailoring MNP surfaces, illuminating their pivotal role in advancing these diverse applications.
The exploration encompasses an array of innovative strategies such as organic coatings, inorganic
encapsulation, ligand engineering, self-assembly, and bioconjugation, elucidating how each approach
impacts or augments MNP performance. Notably, surface-functionalized MNPs exhibit increased
efficacy in multimodal imaging, demonstrating improved MRI contrast and targeted imaging. The
current review underscores the transformative impact of surface modifications on drug delivery
systems, enabling controlled release, targeted therapy, and enhanced biocompatibility. With a compre-
hensive analysis of characterization techniques and future prospects, this review surveys the dynamic
landscape of MNP surface functionalization over the past three years (2021–2023). By dissecting the
underlying principles and applications, the review provides not only a retrospective analysis but also
a forward-looking perspective on the potential of surface-engineered MNPs in shaping the future of
science, technology, and medicine.

Citation: Comanescu, C. Recent Keywords: magnetic nanoparticles; surface functionalization/engineering; theranostics; drug delivery;
Advances in Surface
biomedical applications; targeted therapy; biomolecular conjugation; multifunctional nanoparticles
Functionalization of Magnetic
Nanoparticles. Coatings 2023, 13,
1772. [Link]
coatings13101772
1. Introduction
Academic Editor: Natalia
Magnetic nanoparticles (MNPs) have emerged as versatile entities with profound
V. Kamanina
implications across various scientific frontiers. Their unique physicochemical properties,
Received: 20 September 2023 including superparamagnetism and high surface area-to-volume ratios, have positioned
Revised: 2 October 2023 them as compelling candidates in fields ranging from biomedicine [1,2] to catalysis [3,4].
Accepted: 11 October 2023 However, the strategic engineering of their surfaces by means of surface modifying agents
Published: 15 October 2023 (such as amine, diimide, carboxyl, aldehyde, hydroxyl, etc.) has unlocked a new dimension
of functionalities, allowing further modification by molecule attachment and thus driving
recent advancements and expanding their potential [5].
In the realm of multimodal imaging, the surface functionalization of MNPs has become
Copyright: © 2023 by the author.
a cornerstone in enhancing diagnostic accuracy [6–8]. By judiciously modifying the surface
Licensee MDPI, Basel, Switzerland.
chemistry, researchers have endeavored to optimize their interaction with biological entities,
This article is an open access article
distributed under the terms and
improve biocompatibility, and enhance their imaging contrast properties. This has led to the
conditions of the Creative Commons
development of MNPs with tailored surface coatings, thereby enabling the precise targeting
Attribution (CC BY) license (https://
of specific biomarkers and cell populations. The introduction of functional moieties onto
[Link]/licenses/by/ the MNP surface has not only amplified their potential as magnetic resonance imaging
4.0/). (MRI) contrast agents but has also opened avenues for multimodal imaging techniques,

Coatings 2023, 13, 1772. [Link] [Link]

Coatings 2023, 13, 1772 2 of 36

Coatings 2023, 13, 1772 functional moieties onto the MNP surface has not only amplified their potential as mag- 2 of 31
netic resonance imaging (MRI) contrast agents but has also opened avenues for multi-
modal imaging techniques, merging the power of MRI with other imaging modalities such
as fluorescence
merging or positron
the power of MRIemission
with othertomography (PET).
imaging modalities such as fluorescence or positron
In drug
emission delivery, the
tomography surface functionalization of MNPs has been pivotal in overcom-
(PET).
ing theIn formidable
drug delivery, challenges associated
the surface with efficient
functionalization and targeted
of MNPs has been drug transport
pivotal [9].
in overcom-
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ing the modified
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trolled
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trolled release profiles offers the means
and enhancing thetopharmacokinetics
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release
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catalysts with unparalleled activity and selectivity. This has proven particularly advanta- enabling effi-
cient conversions with reduced side reactions. The advent of well-defined
geous in complex and intricate catalytic transformations, enabling efficient conversions surface architec-
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Thisreview
This reviewnavigates
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therecent
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stridesinin MNP
MNP surface
surface functionalization,
functionalization, unveiling
unveiling
the intricacies of various strategies, their impact on enhancing imaging capabilities,
the intricacies of various strategies, their impact on enhancing imaging capabilities, opti- opti-
mizing drug delivery, and catalytic prowess. The review underscores the interplay
mizing drug delivery, and catalytic prowess. The review underscores the interplay be- between
surfacesurface
tween chemistry and function,
chemistry providing
and function, insightsinsights
providing into the key
into mechanisms underlying
the key mechanisms
these enhancements. Additionally, characterization techniques illuminate the modified sur-
face engineering, shedding light on their structure and behavior. Conex applications such as
cutaneous wound treatment have been shown to be responsive to functionalized hydrogels
based on magnetic core (like Fe3 O4 , MnFe2 O4 and other ferrites) [11]. Despite the strides
Coatings 2023, 13, 1772 3 of 31

made in MNP surface functionalization, several critical challenges persist. Achieving

precise control over surface modifications, understanding the intricate interplay between
surface alterations and functional outcomes, and ensuring long-term stability remain areas
of active investigation. Furthermore, as MNPs traverse the path from laboratory innovation
to clinical application, it is imperative to address issues of biocompatibility, toxicity, and
clinical translatability. These challenges underscore the pressing need for a comprehensive
review that consolidates recent advances in MNP surface functionalization and provides
a roadmap for future research. The interplay between surface chemistry and function
has a clear role in enhancing drug loading and release, improving biocompatibility and
specific targeting and binding, MRI contrast, stimuli-responsive behavior, and reduced ag-
gregation for enhanced stability. For instance, when functionalized with mesoporous silica,
MNPs benefit from a high surface area for drug loading, with high surface areas and pore
volumes affording high drug-loading capacity. Furthermore, stimuli-responsive coatings
like pH-sensitive polymers control drug release, ensuring targeted delivery. On the other
hand, coating MNPs with biocompatible polymers like polyethylene glycol (PEG) creates
a hydrophilic layer that reduces nonspecific protein adsorption, thus preventing recog-
nition by the immune system and leading to prolonged circulation times and enhanced
biocompatibility. Functionalization with targeting ligands, such as folic acid or antibodies,
provides specificity. The functional group’s affinity for receptors on target cells promotes
selective binding, ensuring that the nanoparticles effectively reach and interact with the
desired biological targets. Stimuli-responsive coatings, like pH-sensitive polymers, alter
their conformation and properties in response to changes in environmental conditions. For
instance, in an acidic tumor microenvironment, pH-responsive coatings swell, leading to
controlled drug release. An aspect which is key to successful utilization in biologic systems
is the prolonged stability of MNP formulations; surface coatings with steric hindrance
properties, like PEG, create a barrier that prevents particles from aggregating. The repulsion
between PEG chains on adjacent nanoparticles ensures colloidal stability, particularly in
complex biological environments.
This review aims to address these gaps by presenting a thorough analysis of the recent
strides in the surface functionalization of MNPs. Specifically, the multifaceted strategies
employed to engineer MNPs at the nanoscale are addressed, with a particular focus on or-
ganic and inorganic coatings, ligand exchange mechanisms, and self-assembly approaches.
Through a comprehensive exploration of recent research, this review encapsulates the
burgeoning field of MNP surface functionalization, offering a panoramic view of its recent
and multifaceted applications in the biomedical field. The subsequent sections delve into
specific surface functionalization strategies and their implications in multimodal imag-
ing [12] and drug delivery. The evolving challenges and future prospects are also discussed,
underscoring the transformative potential of surface-engineered MNPs in addressing some
of the most pressing scientific and technological frontiers of our time. In summary, this
review endeavors to synthesize recent advancements in the surface functionalization of
MNPs, providing a holistic perspective on their potential to revolutionize scientific and
medical landscapes. Through analysis of strategies, outcomes, and applications, the aim is
not only to consolidate existing knowledge but also to identify new avenues for research
and innovation in this intriguing field.

2. Synthesis of Magnetic Nanoparticles

The synthesis of magnetic nanoparticles (MNPs) represents a pivotal starting point
in tailoring their properties for diverse applications. The field has witnessed a surge in
innovative approaches to engineer MNPs with precise control over size, shape, crystallinity,
and magnetic properties. While the MNP shape is not a main cause of oxidative stress that
leads to apoptosis, it plays a key role in cellular uptake. Controlling size and morphology
(shape, aspect ratio) can be achieved for most iron oxides (including FeOOH, Fe2 O3 ,
and Fe3 O4 ), given their prime magnetic feature that makes them suitable, among others,
for magnetorheological fluids [13]. One strategy in this sense is to use size-controlling
Coatings 2023, 13, 1772 4 of 31

agents, which effectively also act as surface coating, like polyethyleneimine (PEI) [14].
A concise overview of the prominent synthesis methods and their influence on surface
functionalization will consider the chemical and physical methods described below.
The chemical synthesis route remains a cornerstone in producing MNPs with tunable
characteristics. Co-precipitation, a widely adopted method, involves the controlled precipi-
tation of metal salts in the presence of reducing agents or surfactants; for instance, a mixture
of cation precursors containing Fe2+ and Fe3+ in a stoichiometric ratio can be precipitated
with hydroxide (NH4 OH, NaOH) under a protective atmosphere to yield magnetite Fe3 O4 .
This approach yields monodisperse MNPs with controllable sizes, making it a popular
choice for subsequent functionalization. Similarly, thermal decomposition (polyol method)
involves the decomposition of metal precursors at elevated temperatures, facilitating the
formation of MNPs with narrow size distributions and high crystallinity, oftentimes allow-
ing additional tuning of shape (cubic, hexagonal, etc.) and size (very small NPs of a few
nm and very narrow PDI polydispersity index can be achieved through this route). These
chemically synthesized MNPs offer versatile platforms for surface functionalization due to
their well-defined surfaces and high crystallinity.
Physical methods, such as laser ablation and sputtering, have emerged as viable al-
ternatives for producing MNPs tuned for specific applications. Laser ablation involves
irradiating a target material with high-energy laser pulses, thereby inducing ablation and
condensation of nanoparticles. This technique allows for precise control over size and
composition, enabling tailored surface modifications. For instance, Franzel et al. reported
the synthesis of superparamagnetic MNPs consisting of Fe3 O4 and Fe3 C upon laser ablation
of an Fe foil in ethanol [15]. Superparamagnetism refers to the property exhibited by certain
nanoparticles, particularly magnetic nanoparticles, that do not have a permanent magnetic
moment but that can respond strongly to an external magnetic field, and it represents an
important characteristic for applications like targeted drug delivery and magnetic reso-
nance imaging (MRI). Further modification of the synthesis by altering reaction media
(water, organic solvents) affords variation in the composition of MNPs, including core–shell
structures of type iron–iron oxide, carbon coating, etc. Sputtering, on the other hand,
relies on the ejection of target material atoms by energetic ion bombardment. This yields
MNPs with minimal contamination suitable for subsequent surface engineering, like, for
instance, FeCo NPs of very high saturation magnetization (226 emu/g) or multifunctional
MNPs coated with PEG polyethylene glycol for improved solubility and enhanced biocom-
patibility [16]. Magnetization, as a core principle, refers to the property of a material to
become magnetized in the presence of an external magnetic field. In the case of MNPs, their
small size leads to unique magnetic behaviors. When subjected to an external magnetic
field, the magnetic moments of individual nanoparticles align with the field, resulting in
an overall magnetic polarization. This phenomenon is known as superparamagnetism.
The level of magnetization is influenced by factors such as the size of the nanoparticles
(sheer size, aspect ratio, shape, volume), their composition, and the strength of the applied
magnetic field. Understanding and manipulating magnetization properties is essential
in tailoring the behavior of magnetic nanoparticles for specific applications. The ability
to control magnetization allows for precise targeting of nanoparticles to specific anatomi-
cal sites in magnetic drug delivery. Biocompatibility refers to the ability of a material or
substance to function safely within a biological system without causing harm or adverse
reactions; in this context, MNPs should not elicit harmful responses from the body’s tissues
or immune system.
Biogenic synthesis has garnered attention for its eco-friendly approach and facile
surface functionalization potential. Utilizing microorganisms, plants, or their extracts,
this method harnesses the biological entities’ inherent ability to reduce metal ions and
form MNPs. The resulting MNPs often exhibit unique surface functionalities due to
the biomolecules involved in their synthesis, thus opening avenues for surface modi-
fications [17]. Carvallo et al. reported the use of magnetotactic bacteria to synthesize
magnetosomes coated with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or citric acid
Coatings 2023, 13, 1772 5 of 31

for use in magnetic hyperthermia applications [9,17]; the MNPs coated with citric acid
showed a higher SAR-specific absorption rate and were thus better suited for biomedical
applications [17]. When IONs were synthesized by magnetotactic bacteria and were further
utilized to synthesize magnetosomes coated with citric acid or 1,2-dioleoyl-sn-glycero-3-
phosphocholine (DOPC), the magnetosomes showed reduced magnetostatic interactions
compared to those in neat magnetosomes [17].
The influence of synthesis parameters on MNP surfaces cannot be understated. The
influence of the shape and size of MNPs on their MFH effect has been investigated recently,
concluding that specific synthesis parameters should be met in order to produce the highest
possible SAR and hence the desired effect in MFH; for instance, ellipsoidal NPs with the
highest SAR were found to be those of 10 nm (equatorial size) and an aspect ratio of 2 [18].
The choice of precursor materials, solvents, and reaction conditions significantly affects
the surface chemistry. Organic ligands or capping agents introduced during synthesis can
impart initial surface functionalities, setting the stage for subsequent modifications [19].
Temperature, reaction time, and precursor concentration also dictate MNP properties,
including surface energy and reactivity (Table 1). In a typical synthesis, Fe(II) and Fe(III)
precursors in a 1:2 molar ratio are added to a mixture of oleic acid (OA) and oleylamine
(OAm) in a round-bottom flask and then heated up to 300 ◦ C (depending on the solvent
of choice, benzyl ether, dioctyl ether etc.), after which a dark brown solution is produced.
After cooling and washing (typically with ethanol, C2 H5 OH), stirring and/or sonication
with additional OA can successfully lead to the organic coating of MNPs, which can be
resuspended in organic solvents (hexane or higher alkanes). Additional heating may be
required, after which cooling and separation (usually by a permanent magnet) lead to the
final MNPs that can be dried or stored for further use. It is essential to carry out the co-
precipitation reaction under a protective inert gas atmosphere in order to avoid the further
oxidation of magnetite to hematite. Various modifications of the synthetic procedure are
found throughout the literature, but the core principles remain the same. Notably, detailed
procedures provide a reproducible method for the synthesis of magnetic nanoparticles,
ensuring consistent results for subsequent applications in various fields.
The synthesis of MNPs serves as the foundation for their subsequent surface function-
alization. Chemical, physical, and biogenic synthesis methods offer diverse avenues for
tailoring MNP characteristics, paving the way for precise and effective surface engineering.
Understanding the impact of synthesis parameters on surface properties is paramount for
devising successful surface functionalization strategies in magnetic resonance imaging
(MRI), drug delivery, and catalysis. A concise and brief overview of the synthesis methods
typically employed in MNPs’ synthesis is summarized in Table 1.
The surface properties of magnetic nanoparticles (MNPs) are intricately linked to
the synthesis parameters employed during their fabrication. These parameters include
reaction temperature, precursor concentrations, surfactant types, and reaction times. The
careful manipulation of these factors can yield MNPs with tailored surface characteristics,
influencing their behavior in diverse applications. For instance, studies by Lu et al. [20]
and Majidi et al. [21] systematically investigated the impact of reaction temperature on
MNP surface functionalization while also serving as comprehensive reviews on synthetic
methods of generating MNPs. The results demonstrated a notable increase in the density
of surface functional groups as the temperature was elevated from 100 ◦ C to above 200 ◦ C.
Moreover, reaction times have been shown to impact the size distribution and surface
roughness of MNPs [20].
Surfactant choice and concentration also exert significant control over MNP sur-
face properties; for instance, the use of oleic acid (OA) as a surfactant resulted in a
higher degree of surface coverage compared to other surfactants. The nature of the shell
(organic/inorganic, magnetic or non-magnetic) has an influence on its magnetic properties,
as the ligands can modify the anisotropy and magnetic moment of the metal atoms located
at the surface of the particles [20].
Coatings 2023, 13, 1772 6 of 31

Table 1. Synthetic overview of synthesis methods for MNPs and their main characteristics.

Synthesis Method Description Characterization Tools

In this classic method, metal salts (FeCl3 , FeCl2 )
are dissolved in a solvent (water, ethanol) Transmission electron microscopy (TEM) and
Co-Precipitation followed by the addition of reducing agents X-ray diffraction (XRD) elucidate the core
(NaBH4 , NH3 , NH2 NH2 ). The reduction of structure of MNPs.
metal ions yields MNPs.
Organic metal precursors (iron pentacarbonyl)
Thermal are decomposed at elevated temperatures TEM and XRD reveal their size
Decomposition (200–300 ◦ C) in organic solvents (oleic acid, oleyl and crystallinity.
amine) to generate MNPs.
Water-in-oil microemulsions, containing
surfactants (CTAB) and co-surfactants (butanol,
hexanol), are employed to control MNP Dynamic light scattering (DLS) and UV-Vis
Microemulsion
nucleation and growth. Iron salts (FeSO4 ) in the spectroscopy monitor the reaction progress.
aqueous phase react with reducing agents
(NaBH4 , hydrazine, etc.) to form MNPs.
Silica-coated MNPs are synthesized via
hydrolysis and condensation of silane precursors
FTIR spectroscopy can attest for
Sol-Gel (TEOS) in the presence of MNPs. The resulting
shell formation.
silica shell stabilizes the MNPs and provides
functional groups for subsequent modifications.
Continuous-flow microreactors facilitate
controlled nucleation and growth of MNPs by
In-line spectroscopy monitors the
Microfluidics mixing iron precursors (Fe(acac)3 ) with reducing
reaction kinetics.
agents (hydrazine) under controlled
flow conditions.
Iron precursors (FeCl3 , Fe(acac)3 ) are
hydrothermally treated at elevated temperatures Synthesis Scanning electron microscopy
Hydrothermal (150–300 ◦ C) and pressures (10–100 atm) in a (SEM) and XRD confirm particle morphology
solvent (water, ethylene glycol, benzyl ether) to and crystallinity.
yield crystalline MNPs.
Electrodeposition involves the reduction of iron
Electrochemical techniques monitor the
ions onto an electrode surface. Precursors (iron
Electrochemical Synthesis deposition process, while SEM reveals
salts) are dissolved in an electrolyte solution, and
surface morphology.
an electric current is applied.
Ultrasound irradiation of metal salt solutions The process is monitored by UV-Vis
Sonolysis (FeCl3 ) generates reactive species that reduce spectroscopy, while TEM elucidates their
metal ions to MNPs. morphology and size.
Irradiation of metal salt solutions (FeCl3 ) with Size and composition are determined by
Radiolysis ionizing radiation (gamma rays, electron beams) TEM and inductively coupled plasma mass
induces the reduction of metal ions to MNPs. spectrometry (ICP-MS).
Energy-dispersive X-ray spectroscopy (EDS)
Biogenic Microorganisms (bacteria, fungi) or plant and Fourier-transform infrared spectroscopy
Synthesis extracts reduce metal ions (Fe3+ ) to MNPs. (FTIR) confirm the presence of biomolecules
on the MNP surface.

Furthermore, concentration gradients of precursor materials play a pivotal role in

dictating MNP surface composition, and oftentimes non-stoichiometric ratio is necessary
in order to obtain pure Fe3 O4 (magnetite). These examples highlight the critical role of
quantitative data in elucidating the influence of synthesis parameters on MNP surfaces.
By employing advanced characterization techniques and systematically varying synthesis
conditions, researchers can precisely tailor MNP surface properties, opening avenues for
enhanced performance in applications ranging from drug delivery to catalysis.
Coatings 2023, 13, 1772 7 of 31

Regarding biogenic synthesis of magnetic nanoparticles, there are several potential

concerns associated with their further use in a clinical setting. These concerns primarily
revolve around safety, scalability, and regulatory approval. Biogenic synthesis relies on
living organisms to produce nanoparticles, which introduces variability in terms of particle
size, shape, and surface properties, and hence may not always meet the stringent standards
required for clinical applications. Additionally, this type of synthesis can introduce impuri-
ties or contaminants that could pose risks in a clinical context, particularly if they include
toxic substances or allergens. The use of biogenic synthesis methods may require extensive
regulatory approval processes to ensure safety and efficacy; therefore, standardizing the
synthesis process to meet regulatory standards can be challenging due to the biological
variability inherent in living organisms. Scalability and reproducibility remain current
challenges in order to meet clinical demand. The availability of specific organisms and their
growth conditions may limit the production capacity, and replicating the exact conditions
across different batches can be complex and oftentimes unpredictable. In some cases, the
organisms used in biogenic synthesis may be genetically modified or engineered, which
raises concerns about potential risks to the host organisms as well as the potential release
of genetically modified organisms into the environment. Even though biogenic synthesis
methods aim to produce NPs using biological entities, questions about the biocompatibility
and potential toxicity of the resulting nanoparticles may arise. It is crucial to thoroughly
evaluate the safety profile of biogenically synthesized nanoparticles for clinical use. Ethi-
cal consideration about the use of living organisms for nanoparticle synthesis also raises
some issues related to the potential impact on ecosystems, especially if they are genetically
modified or rare species.
Lastly, biogenic synthesis may lead to nanoparticles with different stability profiles
compared to their chemically synthesized counterparts. Understanding the long-term
stability and storage conditions of biogenically synthesized nanoparticles is crucial for their
clinical viability. In conclusion, while the biogenic synthesis of magnetic nanoparticles
holds promise for various applications, including clinical ones, there are notable concerns
regarding safety, scalability, regulatory approval, and ethical considerations. Thorough
evaluation, standardization, and rigorous testing are essential steps in addressing these
concerns and advancing biogenic synthesis methods towards clinical applications [20,21].
These synthesis methods collectively offer a toolkit for tailoring MNPs with distinct
characteristics, laying the groundwork for subsequent surface functionalization. Character-
ization techniques such as TEM, XRD, FTIR, and spectroscopic methods provide critical
insights into their structural and surface properties, guiding the choice of surface mod-
ification strategies. The synthesis route serves as a pivotal bridge between MNPs’ core
composition and their surface chemistry, enabling a precise design for multimodal imaging,
drug delivery, and catalytic applications.
The novel functionalization strategies discussed in this paper represent significant
advancements over existing methods in terms of both efficiency and effectiveness, tackling
issues such as specificity, safety, biocompatibility, and clinical translation. In terms of
efficiency, these novel strategies enable highly precise targeting of specific cells or tissues.
This surpasses conventional methods, which often rely on passive accumulation through
the enhanced permeability and retention (EPR) effect. The new functionalization techniques
offer unprecedented control over drug release kinetics, surpassing traditional encapsulation
methods that may have limited control over release rates. Surface modifications in the
novel strategies also enhance catalytic activity through tailored active sites, surpassing
generic functionalization which may not optimize the catalytic potential.
In terms of effectiveness, the novel strategies greatly enhance therapeutic precision,
enabling drugs to be delivered precisely where they are needed. This is a significant im-
provement over traditional methods where off-target effects can be a concern. The new
functionalization techniques often lead to enhanced stability and longevity of the function-
alized nanoparticles, surpassing traditional coatings that may be less robust while also
affording the incorporation of multiple functionalities onto a single nanoparticle, allowing
Coatings 2023, 13, 1772 8 of 31

for synergistic effects [8,22,23]. Theranostics refers to combined therapy and diagnostics
and represents a class of technologies that combine therapeutic and diagnostic capabilities
in a single system. Notably, MNPs used in theranostics can both deliver a drug to a specific
site and also be imaged to monitor the drug’s distribution and therapeutic effects. This
strategy outperforms existing methods that may be limited to a single function, and it is
key to offering enhanced multifunctionality. In this context, MNPs are ideal candidates
in theranostic platforms. For instance, MRI-guided NPs have been utilized in combined
photodynamic therapy (PDT) and photothermal therapy (PTT), thus achieving chemical
exchange on the tumor and, respectively, localized thermal damage at the tumor level [8].
Additional strides have been made in order to overcome biologic barriers such as the
blood–brain barrier (BBB), and these consist of various functionalization of penetrating
NPs with CPP (cell-penetrating peptides) such as hydrophilic (cationic; TAT, penetratin,
R8), amphipathic (SynB, RGD, etc.) or hydrophobic (nonpolar, C105Y, PFV, Pep-7) [22]. An
ongoing trend is to utilize MNPs in cell membrane-based biomimetic nanosystems for per-
sonalized disease theranostics including oncology, bacterial infections, brain diseases, and
inflammatory diseases [23]. Theranostics exemplifies how the integration of multiple func-
tionalities in MNPs can lead to highly effective multifunctional platforms. By combining
targeted drug delivery with real-time imaging, researchers can develop personalized and
optimized treatment strategies for cancer patients, minimizing side effects and maximizing
therapeutic outcomes. This approach holds significant promise for the future of precision
medicine in oncology [22,23].
Important advancements have been made in terms of specificity, with stimuli-responsive
coatings in the novel strategies responding to specific cues in the microenvironment, thereby
offering highly specific imaging capabilities. “Stimuli-responsive” describes materials, coat-
ings, or systems that can change their properties or behavior in response to specific external
stimuli; in relation to MNPs, this could refer to coatings that change their structure or re-
lease properties in response to factors like pH, temperature, or light, among other factors.
Traditional contrast agents may lack this level of specificity. Meanwhile, recent strides often
incorporate coatings or ligands that enhance biocompatibility, reducing potential toxicity
concerns, which in turn surpasses older methods that may not have addressed biocompatibil-
ity to the same extent. Finally, the many examples summarized in this review point to their
great promise in clinical applications, with many MNP systems undergoing clinical trials,
surpassing existing methods that may still be in the preclinical stage.
In summary, the novel functionalization strategies discussed in this paper demonstrate
superior efficiency and effectiveness compared to existing methods. They offer a range
of advantages, including enhanced precision, stability, multifunctionality, and improved
biocompatibility, and are poised to redefine various fields, from medicine to catalysis
and beyond.

3. Characterization Techniques
Characterizing the intricate surface modifications of magnetic nanoparticles (MNPs)
is paramount to comprehending their behavior and tailoring them for diverse applica-
tions [24]. This section describes the wide array of characterization techniques typically
utilized to unveil the subtle intricacies of surface functionalization (Table 2).
These techniques collectively decipher the intricate landscape of surface functional-
ization, illuminating the impact of modifications on MNPs’ physicochemical properties.
Rigorous application of these characterization tools and more advanced connected methods
can unveil the nuances of surface engineering, enabling the precise tailoring of MNPs for
specific applications in multimodal imaging, drug delivery, catalysis, and beyond [25].
Coatings 2023, 13, 1772 9 of 31

Table 2. Typical characterization tools used to describe functionalized MNPs.

Characterization Methods Description

TEM offers high-resolution imaging, revealing MNP morphology,
size, and core–shell structures. Contrast variations highlight surface
Transmission Electron Microscopy (TEM) coatings and confirm successful functionalization. Energy-dispersive
X-ray spectroscopy (EDS) coupled with TEM maps elemental
distribution across MNPs.
XPS provides elemental composition information and oxidation states
of surface-functionalized MNPs. Binding energy shifts indicate
X-ray Photoelectron Spectroscopy (XPS)
surface chemical interactions, validating ligand attachment or
shell formation.
FTIR identifies functional groups on MNPs’ surfaces through
vibrational spectra. Shifts in or the appearance of peaks confirm
Fourier-Transform Infrared Spectroscopy (FTIR)
ligand exchange or coating formation. Attenuated total reflection
(ATR) FTIR enables the analysis of solid MNPs.
DLS evaluates the hydrodynamic size and dispersity of
surface-functionalized MNPs in solution. Changes in size or
Dynamic Light Scattering (DLS)
dispersity after functionalization reflect coating stability and
influence on hydrodynamic behavior.
Zeta potential quantifies surface charge of MNPs, revealing
electrostatic interactions between functional coatings and the
Zeta Potential Analysis
surrounding medium. Zeta potential changes indicate successful
charge modification.
Solution-state NMR elucidates surface functional groups and
Nuclear Magnetic Resonance (NMR) molecular dynamics. Ligand exchange or bioconjugation is confirmed
by chemical shift changes or the appearance of new peaks.
UV-Vis spectroscopy reveals ligand-specific absorbance, confirming
UV-Visible Spectroscopy: functionalization. Shifts in absorption bands indicate changes in the
electronic environment due to surface engineering.
SEM provides topographical information on MNP surfaces.
Scanning Electron Microscopy (SEM) Microstructural changes due to functionalization, such as shell
formation or aggregation, are discerned.
Superconducting quantum interference device (SQUID)
Magnetic Measurements magnetometry quantifies magnetic behavior, confirming core–shell
architecture and magnetic moments of surface-functionalized MNPs.
XRD verifies MNP crystallinity and phase changes due to
X-ray Diffraction (XRD) functionalization. Shifts in or broadening of diffraction peaks indicate
surface modifications or encapsulation.

4. Surface Functionalization Strategies

Surface functionalization of magnetic nanoparticles (MNPs) constitutes a transfor-
mative approach, enabling tailored modifications that unlock their potential in diverse
applications. This section expands on the array of surface functionalization strategies,
elucidating their principles, advantages, and outcomes in MR imaging, drug delivery, and
catalysis as some of the main applications of surface-functionalized MNPs. Below is a table
summarizing the most widespread methods used to functionalize MNPs, according to
their type of coating (organic, inorganic), specific precursors, and materials used, and the
suitable characterization methods (Table 3).
Coatings 2023, 13, 1772 10 of 31

Table 3. Summary of functionalization strategies for MNPs.

Type of Precursors/Materials and Characterization

Observations
Functionalization Short Description of Method Techniques
This imparts colloidal stability,
Organic ligands, such as citrate,
biocompatibility, and modulates Dynamic light scattering
polyethylene glycol (PEG), or
surface charge. The enhanced (DLS) and zeta potential
polymers, are grafted onto
Organic Coatings dispersibility of MNPs in measurements verify the
MNPs’ surfaces through
biological media facilitates their stability and
covalent or
utilization in drug delivery and charge modification.
non-covalent interactions.
targeted imaging.
MNPs are encapsulated within
inorganic materials like silica,
gold, or metal oxides. These Silica-coated MNPs, for
Transmission electron
shells enhance stability, protect instance, offer a platform for
microscopy (TEM) and X-ray
Inorganic Shells MNPs from degradation, and versatile surface
photoelectron spectroscopy
enable bioconjugation. For functionalization and controlled
(XPS) confirm shell formation.
instance, core–shell Fe3 O4 /Pt drug release.
MNPs have been obtained via
silylation/polymerization [26].
The exchange of native surface This strategy enables targeted
ligands with functional drug delivery through the Fourier-transform infrared
Ligand Exchange molecules (amines, thiols) conjugation of targeting ligands spectroscopy (FTIR) confirms
allows for precise control over or the attachment of successful ligand exchange.
MNP properties. therapeutic payloads.
DNA-functionalized MNPs, for
MNP surface functionalization
instance, enable programmable Gel electrophoresis and
can exploit the self-assembly of
Self-Assembly interactions, leading to fluorescence assays validate
molecules (DNA, peptides) onto
controlled aggregation self-assembly.
the MNP surface.
or dispersal.
MNPs are conjugated with
Antibody-conjugated MNPs Enzyme-linked
biomolecules (antibodies,
offer exquisite cellular or immunosorbent assays
Bioconjugation peptides) through affinity
molecular targeting in imaging (ELISA) confirm successful
interactions, yielding specific
and drug delivery. bioconjugation.
targeting capabilities.
Azide-terminated MNPs react
Bioorthogonal reactions (click Copper-catalyzed or
with alkyne-modified
Click Chemistry chemistry) facilitate specific and copper-free click reactions
molecules, yielding stable and
robust surface functionalization. validate successful coupling.
versatile conjugates.
Sequential deposition of Quartz crystal microbalance
This approach enables the
polyelectrolyte layers onto (QCM) and UV-Vis
Layer-by-Layer Assembly controlled release and
MNPs yields multifunctional spectroscopy monitor
modulated surface charges.
coatings. layer-by-layer assembly.
Stimuli-responsive polymers
(pH, temperature) can be The swelling behavior of
grafted onto MNP surfaces, Suitable for controlled polymers is probed using
Responsive Polymers
facilitating controlled drug drug release dynamic light scattering (DLS)
release in specific and turbidimetry.
microenvironments [27].
Cyclodextrins or cucurbiturils
form host–guest complexes Nuclear magnetic resonance
Suitable for controlled
Host-Guest Systems with molecules on MNP (NMR) and UV-Vis
drug release
surfaces, enhancing stability spectroscopy
and enabling controlled release.

The surface functionalization of magnetic nanoparticles (MNPs) is a pivotal step that

imparts them with specific functionalities, thereby enabling their use in diverse applications.
Coatings 2023, 13, 1772 11 of 31

Several strategies have emerged, each with distinct advantages and limitations. Inorganic
shells, for instance, exhibit enhanced stability and offer tunable properties by varying the
composition and thickness of the inorganic shell. However, their synthesis can involve
multi-step processes and requires precise control over reaction conditions, which can be
more complex compared to other strategies, and there is a potential for core–shell mismatch,
which can make seamless integration challenging. The ligand exchange variant allows for
versatility due to the wide range of ligands available and can be carried out under mild
conditions, thus minimizing the potential damage to the magnetic core. On the downside,
the stability can be limited, as ligands might detach over time, and thus specific control
over shell thickness can be challenging.
These strategies underscore the transformative impact of surface functionalization,
enabling MNPs to transcend their innate capabilities. Characterization techniques like
TEM, FTIR, and spectroscopy play a pivotal role in verifying successful functionalization,
guiding the design of MNPs tailored to specific applications. As we delve further into this
review, we explore the role of these strategies in enhancing multimodal imaging, drug
delivery, and catalysis, illuminating the dynamic interplay between surface engineering
and diverse applications.

5. Surface Functionalization for Drug Delivery

The strategic surface functionalization of magnetic nanoparticles (MNPs) has revolu-
tionized drug delivery, enabling precise and efficient therapeutic interventions. This section
delves into the multifaceted enhancements brought about by surface engineering, including
controlled drug release, targeted delivery, and overcoming biological and histohematic
barriers [22]. Responsive and targeted drug delivery based on MNPs (magnetite Fe3 O4
mainly) coated with polymers and biopolymers [28], biomolecules or macromolecules
(5-fluorouracil (5-FU), oxaliplatin, and irinotecan), can be successfully used for the treat-
ment of various types of cancer, such as in colorectal cancer therapy [29]. A brief timeline
overview starting from the SiO2 coating of magnetite in 1985 is depicted in Figure 2 [29].
Inorganic shells such as SiO2 (silica) still remain one of the preferred surface functional-
ization routes, especially for MNPs like γ-Fe3 O4 [30]. Recent advances in nanoscience
greatly benefit from the introduction of NPs and magnetic iron oxide nanoparticles in
particular, owing to their unique set of properties and many advantageous biomedical
applications [31], extending their use to stem cell biotechnology [32].
Various polymers have been employed for coating inorganic NPs (such as a Pt
shell [26]), and MNPs in particular, such as hydrophilic polymers (like functional polyaspar-
tamide [33]) that help them achieve water-solubility. Moreover, the stability of magnetite
NPs obtained by Massart synthesis (co-precipitation of Fe(II) and Fe(III) precursors) was
studied by Klekotka et al. [34], including their surface-functionalized counterparts, specifi-
cally SiO2 -covered Fe3 O4 (SiO2 @Fe3 O4 ) or magnetite grown on pre-formed Fe3 O4 seeds
(Fe3 O4 @Fe3 O4 ) in polyol synthesis using oleyl amine/oleic acid as stabilizers and surface
protection agents [34]. An overview of the main research direction currently being taken by
the research community is given in Figure 3.
Surface modifications offer unprecedented control over drug release kinetics. Drug-
loaded MNPs encapsulated within stimuli-responsive polymers (pH, temperature) exhibit
on-demand drug release triggered by specific microenvironment cues [27]. The rate and
extent of drug release are characterized using in vitro release assays. Surface-functionalized
MNPs offer unparalleled targeting precision. The conjugation of targeting ligands (antibod-
ies, peptides) guides MNPs to specific cell receptors or tissues, minimizing off-target effects.
In vitro cell binding assays and in vivo biodistribution studies validate targeted delivery
efficiency. Biodistribution refers to how a substance, like a nanoparticle, is distributed
throughout the body, and this encompasses where the substance moves, how much of it
accumulates in different tissues or organs, and how long it stays there.
Coatings 2023, 13, 1772 12 of 31
Coatings 2023, 13, 1772 12 of 36

Coatings 2023, 13, 1772 Figure 2. The timeline of magnetic nanoparticles in therapeutic and imaging application. Reprinted
13 of 36
Figure 2. The timeline of magnetic nanoparticles in therapeutic and imaging application. Reprinted
from reference [29] under a Creative Commons Attribution 4.0 International License.
from reference [29] under a Creative Commons Attribution 4.0 International License.
Various polymers have been employed for coating inorganic NPs (such as a Pt shell
[26]), and MNPs in particular, such as hydrophilic polymers (like functional polyaspar-
tamide [33]) that help them achieve water-solubility. Moreover, the stability of magnetite
NPs obtained by Massart synthesis (co-precipitation of Fe(II) and Fe(III) precursors) was
studied by Klekotka et al. [34], including their surface-functionalized counterparts, spe-
cifically SiO2-covered Fe3O4 (SiO2@Fe3O4) or magnetite grown on pre-formed Fe3O4 seeds
(Fe3O4@Fe3O4) in polyol synthesis using oleyl amine/oleic acid as stabilizers and surface
protection agents [34]. An overview of the main research direction currently being taken
by the research community is given in Figure 3.

Figure
[Link]
Representativeresearch direction
research in functionalized
direction magnetic
in functionalized nanoparticles.
magnetic nanoparticles.

Surface modifications offer unprecedented control over drug release kinetics. Drug-
loaded MNPs encapsulated within stimuli-responsive polymers (pH, temperature) ex-
hibit on-demand drug release triggered by specific microenvironment cues [27]. The rate
and extent of drug release are characterized using in vitro release assays. Surface-func-
tionalized MNPs offer unparalleled targeting precision. The conjugation of targeting lig-
Coatings 2023, 13, 1772 13 of 31

Tissue engineering and regeneration has been shown to be possible by Chitosan

(CS)-based NP formulations, including CS/ferromagnetic scaffolds, owing to the efficient
interaction of -NH2 groups (CS) with the MNPs’ polymeric coating [35]. Such effective
CS-coating of the magnetite magnetic core also prevents further oxidation of magnetite
Fe3 O4 to hematite Fe2 O3 . Biomedical applications of MPNs and SPIONs in particular have
been recently reviewed by Jiang et al. related to their synthesis, in vivo protein detection,
magnetic heating/MFH [36], and in vivo imaging and drug delivery [1]. Treatment of
degenerative diseases can potentially be modulated by Wnt signaling and has inspired
Hu et al. to immobilize Wnt fragment peptides on MNPs with promising results on human
embryonic kidney (HEK293) Luc-TCF/LEF reporter cell line [37].
Surface engineering influences cellular uptake mechanisms, thereby enhancing drug
internalization. Ligand-decorated MNPs undergo receptor-mediated endocytosis, improv-
ing drug delivery to intracellular compartments. Confocal microscopy and flow cytometry
quantify enhanced cellular uptake. Surface-engineered MNPs enable intracellular drug
delivery. Cell-penetrating peptides facilitate direct entry into cells, bypassing endocytotic
pathways. Intracellular imaging and drug efficacy assays validate efficient intracellular
drug delivery. These surface modifications enable MNPs to traverse biological barriers [22].
Stealth coatings (PEG) reduce opsonization, prolonging blood circulation, and enable pas-
sive accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect.
Pharmacokinetic studies and tumor accumulation assays validate EPR-driven delivery.
Surface functionalization permits the simultaneous loading of multiple drugs onto
MNPs. Conjugation of distinct drug molecules or payloads enables combination therapy,
targeting multiple pathways simultaneously. In vitro cytotoxicity assays elucidate syner-
gistic therapeutic effects. Surface-functionalized MNPs facilitate personalized medicine
approaches. Patient-specific targeting ligands enable tailored drug delivery, minimizing
adverse effects and enhancing therapeutic outcomes. Genomic and proteomic profiling
guide the design of personalized MNPs, while biomimetic approaches [14] enhance the
outcome in various diseases such as brain cancer and inflammatory and bacterial infec-
tions [23]. Biomimetic NPs can also be used as cost- and time-effective magnetic biosensors,
and they can concentrate Gram-positive and Gram-negative microorganisms for easier
bacterial detection to concentrations as low as 10 CFU/mL using qPCR [14].
MNPs equipped with responsive coatings release drugs in response to external stimuli
(magnetic field, light) [27,38]. Magnetic hyperthermia-triggered drug release exploits
localized heating induced by alternating magnetic fields. Temperature measurements
validate controlled release [5,9,17,39,40]. Dual-functional MNPs merge drug delivery with
therapeutic modalities. The conjugation of chemotherapeutic drugs with photosensitizers
or gene therapy agents [41] offers synergistic treatment approaches. Cell viability assays
and in vivo tumor regression studies demonstrate combination therapy efficacy.
Surface-functionalized MNPs have entered clinical trials, demonstrating promise in
cancer therapy and beyond. The translation of these advanced platforms from preclinical
studies to clinical practice requires rigorous safety assessments, optimization of targeting
strategies, and scalable production techniques. While base nanoparticles pose several
potential shortcomings and toxicity-related issues, functionalized NPs alleviate many of the
main downsides preventing the use of MNP-based nanoplatforms: reactive oxygen species
(ROS) generation, targeted delivery, and biodegradation. For instance, conjugated polymer
nanoparticles (CPNs) modified with dopants (like iron oxide) behave as theranostic agents
with prospects for multifunctionality in imaging and treatment [42]. Arias-Ramos et al. syn-
thesized by nanoprecipitation conjugated polymer nanoparticles CPNs based on 2 nm-thick
oleic acid-caped MNPs (NiFe2 O4 , Fe3 O4 of ~5 nm) and fluorescent conjugated polymer (CP)
poly(9,9-dioctylfluorene-alt-benzothiadiazole, F8BT) or polystyrene grafted with ethylene
oxide functionalized with carboxyl groups (PS-EG-COOH), with good results towards
glioblastoma (GBM, a common tumor of the central nervous system) using light delivery
to the brain tissue by means of fiber optics [42].
Coatings 2023, 13, 1772 14 of 31

Simulations using quantum chemistry (DFT) have also been performed, for instance
Coatings 2023, 13, 1772 on the system of tirapazamine (TPZ, anticancer drug) and the magnetic nanoparticle 15 of 36
(MNP) Fe6 (OH)18 (H2 O)6 , where the interaction between the MNP and TPZ was shown to
be facilitated by intraring N-atom, -NH2 , and -NO groups present in the TPZ molecule,
Coatings 2023, 13, 1772 concluding that interaction energetics via the first two are more accessible than via15the
of 36
-NO
moiety [43]. There were two envisioned pathways for the covalent binding of TPX onto
MNPs via their surface -OH hydroxyl groups (Figure 4).

Figure 4. TPZ–MNPs binding via -NH2 or -NO mechanisms.

Figure
[Link]–MNPs
TPZ–MNPs binding via -NH
binding via -NH22or
or-NO
-NOmechanisms.
mechanisms.
Other functionalization strategies focused on the polymer coating of magnetite NPs
by atom
Other transfer radical polymerization (ATRP)on inthe
order to yield magnetic functionalized
Otherfunctionalization strategiesfocused
functionalization strategies focused on the polymer
polymer coating
coating ofof magnetite
magnetite NPsNPs
supports
by atom of the
transfer general
radical formula Fe
polymerization 3 O 4 @MSN-PDMAEMA-FA
(ATRP) in order to yield of ~180
magnetic nm to be used for
functionalized
by atom transfer radical polymerization (ATRP) in order to yield magnetic functionalized
Dox (doxorubicin)
supports drug loadingFe Dox@Fe 3O4@MSN-PDMAEMA(-FA). These drug deliv-
supportsof ofthe
the general
general formula
formula Fe33O O44@MSN-PDMAEMA-FA
@MSN-PDMAEMA-FA ofof ~180
~180 nmnm to to
be be used
used forfor
ery systems
Dox were tested against breast3 O cancer cells (MCF-7) and resistant cancer cells
Dox(doxorubicin)
(doxorubicin)drug drugloading
loadingDox@Fe
Dox@Fe3O44@MSN-PDMAEMA(-FA).
@MSN-PDMAEMA(-FA). These These drug
drug delivery
deliv-
(MCF-7
systems ADR)
were [44].
tested Beagan
against et al.
breastused magnetic
cancer cells mesoporous
(MCF-7) and silica nanoparticles
resistant
ery systems were tested against breast cancer cells (MCF-7) and resistant cancer cells cancer (MMSNs)
cells (MCF-7
coated
ADR)
(MCF-7 with
[44].
ADR) pH-responsive
Beagan
[44]. et al. used
Beagan polymer
magnetic
et al. 2-Diethyl
mesoporous
used magnetic amino
silicaethyl
mesoporous methacrylate
nanoparticles (MMSNs)
silica nanoparticles (DEAEMA)
(MMSNs)coated
grafted
with by surface-initiated
pH-responsive polymer ARGET
2-Diethylatom transfer
amino ethylradical polymerization
methacrylate
coated with pH-responsive polymer 2-Diethyl amino ethyl methacrylate (DEAEMA) (DEAEMA) (ATRP); these
grafted
surface-functionalized
by surface-initiated ARGETMMSNs atom were further
transfer modified
radical by anionic
polymerization
grafted by surface-initiated ARGET atom transfer radical polymerization (ATRP); these groups’
(ATRP); functionalities
these surface-
functionalized
that would thenMMSNs covalently
surface-functionalized were
MMSNs bindfurther
were modified
FA (folic
further acid) bya anionic
as
modified targeting
by anionicgroups’
agent functionalities
[44].
groups’ The functionali-
functionalities that
would
zation then covalently
strategy
that would thenused bind bind
is shown
covalently FAin(folic
Figure
FA acid)
(folic as aafforded
5, acid)
and targeting
as agent [44].[44].
long-circulation
a targeting agent TheThefunctionalization
time for the smart
functionali-
strategy
drug used is
delivery
zation strategy shown
system.
used in Figure
is shown 5, and5,afforded
in Figure long-circulation
and afforded long-circulation timetime
for the smart
for the drug
smart
delivery system.
drug delivery system.

Figure
Figure5.
Figure [Link]
Synthesis procedure
Synthesis procedure for poly(2-(diethylamino)
procedure for poly(2-(diethylamino)ethylmethacrylate)
poly(2-(diethylamino) ethylmethacrylate) brushes
brushes
ethylmethacrylate) capped
capped
brushes with
with
capped with
folic
folic acid
acid grafted
grafted on
on magnetic
magnetic mesoporous
mesoporous silica
silica nanoparticle
nanoparticle (MMSNs)
(MMSNs) surfaces
surfaces via
folic acid grafted on magnetic mesoporous silica nanoparticle (MMSNs) surfaces via SI-ARGET via SI-ARGET
SI-ARGET
ATRP [44].
ATRP[44].[44].
ATRP

The
The functionalization
Thefunctionalization strategyoutlined
functionalization strategy
strategy outlinedinin
outlined inFigure
Figure
Figure 5,
5,5, involving
involving
involving the
thethe synthesis
synthesis
synthesis of poly(2-
poly(2-
of poly(2-
of
(diethylamino) ethylmethacrylate)
(diethylamino) ethylmethacrylate) (PDEAEMA)
(PDEAEMA) brushes
brushes capped
cappedwith
withfolic
ethylmethacrylate) (PDEAEMA) brushes capped with folic acid grafted acid
folic grafted
acid on on
grafted
magnetic mesoporous silica nanoparticles (MMSNs) surfaces via SI-ARGET
magnetic mesoporous silica nanoparticles (MMSNs) surfaces via SI-ARGET ATRP, offers ATRP, offers
severaldistinct
several distinct advantages
advantages related
relatedtototailored
tailoredsurface
surfacefunctionality,
functionality, grafting density,
grafting en- en-
density,
hanced biocompatibility, specific targeting via folic acid, combined magnetic
hanced biocompatibility, specific targeting via folic acid, combined magnetic and meso- and meso-
porousfeatures,
porous features, and
and potential
potentialforforimaging
imagingapplications.
applications. The
Theuse of of
use surface-initiated
surface-initiatedatomatom
transfer radical polymerization (SI-ARGET ATRP) enables precise control over the
Coatings 2023, 13, 1772 15 of 31

on magnetic mesoporous silica nanoparticles (MMSNs) surfaces via SI-ARGET ATRP, of-
fers several distinct advantages related to tailored surface functionality, grafting density,
enhanced biocompatibility, specific targeting via folic acid, combined magnetic and meso-
porous features, and potential for imaging applications. The use of surface-initiated atom
transfer radical polymerization (SI-ARGET ATRP) enables precise control over the graft-
ing process, allowing for customization of the surface with PDEAEMA brushes and folic
acid, thereby providing tailored surface functionality. SI-ARGET ATRP is known for its
ability to achieve high grafting densities, ensuring a densely packed layer of PDEAEMA
brushes on the MMSNs surface. The incorporation of PDEAEMA brushes enhances the
biocompatibility of the MMSNs. PDEAEMA is a pH-responsive polymer that becomes
protonated under acidic conditions, mimicking the slightly acidic environment of cancer
cells, and this property can aid in the selective targeting of cancer cells. More specifically,
in an acidic environment, such as within the endosomes or lysosomes of cancer cells, the
PDEAEMA brushes undergo protonation, leading to swelling and the subsequent release of
encapsulated drugs. Through further conjugation via folic acid, this strategy targets cancer
cells due to its high affinity for folate receptors, which are overexpressed on the surface
of many cancer cells. The presence of folic acid on the MMSNs’ surface ensures specific
binding and uptake by cancer cells, maximizing therapeutic efficacy [44]. The MMSNs pos-
sess both magnetic properties and a mesoporous structure, thereby allowing for magnetic
guidance to target sites, and provide a high surface area for drug loading, thus enabling
multifunctional drug delivery platforms. Furthermore, the magnetic properties of MMSNs
offer the potential for imaging applications, such as magnetic resonance imaging (MRI).
This dual functionality allows for theranostic applications, where therapy and imaging are
integrated into a single platform, making this approach highly promising for targeted drug
delivery in cancer therapy.
Magnetic nanoplatforms are currently enhanced by loading with enzymes, affording
easier recovery and reutilization as well as improved stability and catalytic activity [45].
Belleti et al. synthesized hybrid Au/Fe3 O4 NPs of ~15 nm mean diameter using L-cysteine
(Cys) as the polymer capping agent or dithiol-terminated polyethylene glycol (PEG(SH)2 ),
yielding NPs of type PEG(SH)2 Au/F3 O4 NPs or CysAu/F3 O4 NPs [46]. These nanoparticle
systems were further conjugated with luciferase enzymes able to catalyze bioluminescent
reactions (Pyrearinus termitilluminans green-emitting click beetle luciferase, PyLuc and
Phrixotrix hirtus red-emitting railroad worm luciferase, RELuc). A brief overview of the
current landscape in MNP coating and functionalization is given in Table 4.

Table 4. Functionalization of various types of MNPs with main applicability in drug delivery.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
Conjugated polymer
UV-VIS, DLS, TEM,
poly(9,9-
MRI evaluation, Theranostic agents
dioctylfluorene-alt-
cytotoxicity in vitro with prospects for
benzothiadiazole,
NiFe2 O4 , Fe3 O4 of Oleic acid coating (U-87 MG and T98G Glioblastoma (GBM); multifunctionality in
F8BT) or polystyrene [42]
~5 nm (2 nm) cells, MTT MR imaging (MRI) imaging and
grafted with ethylene
and Live/Dead cell treatment; preclinical
oxide functionalized
viability assays), MRI studies
with carboxyl groups
fluorescence imaging
(PS-EG-COOH)
Drug binding via
magnetic nanoparticle Anticancer (not
– Tirapazamine (TPZ,) DFT study intraring N-atom, [43]
Fe6 (OH)18 (H2 O)6 evaluated)
-NH2
Fe3 O4 @MSN- SEM, TEM, FTIR, Excellent
Anticancer (MCF-7,
PDMAEMA-FA MSN-PDMAEMA-FA DOX (doxorubicin) surface area, TGA, biocompatibility, [44]
and MCF-7 ADR cells)
(~180 nm) XPS, UV, DLS minimally toxicity
L-cysteine (Cys);
FTIR, FESEM, 48% activity
Au/Fe3 O4 NPs dithiol-terminated Enzymatic activity,
Luciferase (enzyme) luminescence, preservation in case of [46]
(15 nm diameter) polyethylene glycol luminescence activity
bioluminescence CysAuNPMag
(PEG(SH)2 ),
Coatings 2023, 13, 1772 16 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
SPIONs@citrate TEM, Magnetic Anticancer; Magnetic delivery of
Superparamagnetic
(52–58 nm susceptibility, infiltration of SPIONs immune cells
Iron Oxide
Citrate coating hydrodynamic Z size) hydrodynamic into primary human (dynamic [47]
Nanoparticles
loaded into human T Z-average size, zeta CD3+ T cells regime)—potential
(SPIONs)
cells (27 or 80 µg/mL) potential (1,4 pg Fe/cell)) future application
Water-dispersible NPs
MRI; T1 -imaging,
0olyol synthesis from obtained when
maghemite (γ-Fe2 O3 ), IONPs@DEG obtained T2 -imaging (high
Fe(acac)3 and TEM, XPS, XRD, T = 190◦ , 220◦ and
magnetite (Fe3 O4 ) with continuous relaxivities [48]
diethylene glycol magnetization 235 ◦ C (higher T leads
10.9 ± 1.6 nm growth method r2 :163.4 mM−1 s−1 ,
(DEG) to agglomeration);
r1 :135.0 mM−1 s−1 )
high wt% C (XPS)
Magnetosomes with
high encapsulation
biological magnetite
Amphotericin B, AmB efficiencies and drug
nanoparticles (BMs), Controlled drug
Glutaraldehyde GA, (to yield loadings (0.1‰ PLL:
by magnetotactic release, magnetic
poly-L-lysine PLL BM–PLL–AmB and TEM, FTIR 52.7%, and 25.3 mg [49]
bacteria Magnetovibrio hyperthermia (in PBS
(linking reagents) BM–PLL–GA–AmB per 100 mg; while
blakemorei strain media)
conjugates) 0.1‰ PLL–GA 12.5%:
MV-1T
45.0%, 21.6 mg per
100 mg)
Chitosan CS coating
Telmisartan (TEL), validated by FTIR and
yielding FTIR, TGA, XRD, TGA data. Grafting
MNP–CS–TEL TEL is FE-SEM (field TEL, a poorly soluble
Anticancer drug
an angiotensin II emission scanning drug, on the
Magnetic therapy, as carriers of
receptor blocker electron microscope), surface-coated of
nanoparticles (MNPs) Chitosan (CS) Telmisartan (TEL); [50]
(ARB), treating high TEM, VSM (vibrating MNPs (MNP-CS) by
of Fe3 O4 tested against PC-3
blood pressure, heart sample amide bond between
human prostate cancer
failure, diabetic magnetometer), BET amino groups of
kidney disease, surface area analyzer chitosan CS and
and cancer carboxylic groups
of TEL
Environmental Proteolytic hydrolysis
Magnetic
scanning electron (amide bond breaking)
nanoparticles
microscopy (ESEM), in presence of
(maghemite NPs) on Silanization by means Protein padding of
energy dispersive Drug delivery and cathepsin B- protease
anodic alumina of (3-aminopropyl) albumin-fluorescein
X-ray (EDX); FTIR biosensing (growth and initial [51]
nanotubes, to give triethoxysilane isothiocyanate
(ATR), ζ-potential, applications stages of tumor
magnetic anodic (3-APTES, 99%) conjugate (FITC-BSA)
dynamic light metastasis), releasing
alumina nanotubes
scattering (DLS); TEM, fluorescent fragments
(MAANTs)
fluorescence of the protein
Functionalization with
Catalysis (anionic Covalent linkage of an
Sulfonated Arene
Cobalt Carbon-coating, yields FTIR, SEM, elemental ROP of glycidol), or in situ generated
Derivatives via [52]
Nanoparticles CCo nanoparticles analysis recyclable diazonium on the
aqueous in situ
anticoagulant graphene-like surface
diazotization reaction
Mesoporous silica pH-sensitive
(SBA-15), To yield PEI FTIR, TGA, XRD, Targeted delivery to mesoporous magnetic
Fe3 O4 nanoparticles
grafted Doxorubicin (DOX) VSM, SEM, EDX, MCF-7 cell line (breast and biocompatible [53]
(MNPs)
Fe3 O4 @SiO2 @SBA-15 UV-Vis cancer) nanocarrier, high
labeled FA internalization
Click chemistry
SiO2 -NH2 coating, Biomedicine and
affords covalent
alkyne surface catalysis –conversion
XRD, FTIR, TEM, bonding between
functionalization to of glycerol into DHA;
Azide-functionalized SEM, immobilization azide and alkyne
Fe3 O4 yield magnetic Tested against [54]
E. Coli yield (Y), activity groups;
nanoparticle recombinant E. coli
recovery (E), immobilization yield
Fe3 O4 @SiO2 -NH2 - harboring glycerol
83%, activity
alkyne dehydrogenase
recovery 94%
Colloidal stability,
DLS: Z-potential,
Glutathione
HR–TEM, (S)TEM, NPs were found to not
(GSH)-capped on
SEM, EDX, FTIR, Biomedical be toxic at typically
Au/Fe hybrid gold-magnetic- – [55]
Photoluminescence applications used concentrations
iron-oxide NPs
(PL) excitation and (1.5 µg/mL)
(Au-Mag-GSH)
emission spectra,
cytotoxicity
Coatings 2023, 13, 1772 17 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
Branched
Superparamagnetic
polyethyleneimine Cancer treatment:
SEM-EDS, TEM, XRD, nano-rods tested
(BPEI) to yield glioblastoma brain
Superparamagnetic FT-IR, TGA, GC-MS, against U87 human
PEI-coated Fe3 O4 Carnosine dipeptide tumors (GBM);
iron oxide nano-rods DLS, zeta potential, glioblastoma
nano-rods; (β-alanine and inhibition of [56]
(IONRs) based on magnetic properties astrocytoma cell line.
cyclohexane layer L-histidine) post-surgery
magnetite (by whole body 1.5 T Carnosine was fully
prevents NPs metastasis; MRI
MRI system) released by mild
oxidation during monitoring
hyperthermia (40 ◦ C)
synthesis
Synthesis of Ag-
doped Ni ferrite
nanoparticle; PEG was
Polyethylene glycol XRD, FTIR, SEM,
Ag(1-X) NiX Fe2 O4 Curcumin Drug delivery used as a solvent [57]
(PEG) TEM, VSM, UV-Vis
during synthesis;
curcumin loading was
pH-dependent
Immobilized metal BSA binding fitted
No
DLS, FT-IR, TEM, affinity Langmuir isotherm;
NiFe2 O4 (~5 nm) pre-functionalization Serum albumin (BSA) [58]
SAED chromatography of high capacity 916 mg
required
proteins (IMAC) BSA/g dried NPs
Polymers: Protein corona
TEM, TGA/DSC, DLS,
Poly(2-ethyl-2- formation on
Isothermal Titration
oxazoline) (PEtOZ); poly(2-alkyl-2-
Opsonins and Calorimetry, Biomedical
SPIONs Poly(2-ethyl-2- oxazoline)-grafted [59]
Albumin ProtParam tool applications
oxazoline-co-2- SPIONs depends on
(Computation of
isopropyl-2-oxazoline) protein size, flexibility,
Protein Properties)
(PEtIOZ) and charge
MNPs based on Streptavidin- Oligonucleotide-
Fluorescence, AC Circle-to-circle Newcastle disease
commercial 75%–80% functionalized, functionalized
Susceptibility amplification (C2CA)’ virus and Salmonella [60]
(w/w) Fe3 O4 encapsulation with (stability test 92% after
diagnostic as target sequences
(diameter 100 nm) hydroxyethyl starch 3 months at 4 ◦ C)
PEG/neridronate with Improved colloidal
PEG of 2000 or TEM, SAED, EDX, Antioxidant, MRI stability in PBS,
γ-Fe2 O3 /CeO2
5000 Da, producing EELS, DLS, tracing (high r2 enhanced
Maghemite(seeds)/ – [61]
γ-Fe2 O3 /CeO2 @- relaxometry, relaxivity); theranostic biocompatibility;
cerium oxide MNPs
PEG2k and γ- fluorescence platform CeO2 —radical
Fe2 O3 /CeO2 @PEG5k scavenger
MNPs synthesized by
co-precipitation/
Oleic acid (OA), silica microemulsion
(TEOS), cationic method;
polymer P poly[N- Fe3 O4 /SiO2 /P(NIPAM-
Antibacterial (Shigella
isopropylacrylamide- TEM, XRD, FTIR, coAMPTMA).
iron oxide Fe3 O4 boydii, Bacillus cereus,
co-(3- Vancomycin (Van) TGA, SEM, DLS, Vancomycin (Van) [62]
MNPs Staphylococcus aureus
acrylamidopropyl) magnetization curves creates stronger
and Escherichia coli)
trimethylammonium H–bonding between
chloride], P(NIPAm- Van and C-Terminal
co-AMPTMA) L-lysyl-D-alanyl-D-
alanine
of bacteria
SPIONs with
TEM, XRD,
spherical, cuboidal
Superparamagnetic Electrophoretic
(SARmax ) or rod-like
Iron Oxide HAD/OA ratio mobility Hyperthermia (MH,
– shape; efficient MFH [63]
Nanoparticle SPIONs changes MNPs shape measurements, MFH)
(rt to 45 ◦ C, in 60 s,
(Fe3 O4 , 40 nm size) magnetization,
20 kA/m,
SAR/hyperthermia
136–205 kHz)
Configurations
optimized at
Computational optimized at
iron oxide 5-aminolevulinic acid
– study/quantum Anticancer therapy B3LYP/6-31G(d,p) in [64]
nanoparticle (ION) (ALA)
chemistry aq. solution;
H-bonding plays a
central role
Fluorescence, Förster Dehydropeptide-
Citrate-stabilized resonance energy based supramolecular
MNPs manganese
(14.4 ± 2.6 nm), transfer (FRET), Drug delivery/release; magnetogels;
ferrite (MnFe2 O4 ), Doxorubicin (Dox) [65]
lipid-coated STEM, XRD, Raman, theranostic improved drug release
spinel structure
(8.9 ± 2.1 nm) SQUID, rheology, of lipid-coated vs.
UV-Vis, hyperthermia citrate-coated MNPs
Coatings 2023, 13, 1772 18 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
γ0 -Fe4 N have 3 times
The first report of
Envisioned higher saturation
γ0 -Fe4 N (prepared by surface-modified iron
PPMS (Ms, Hc), XRD, biomedical magnetizations than
gas nitridation from nitrides;
– TEM, DLS, FTIR, applications (DNA, IONPs (HC = 310 Oe, [66]
commercial γ-Fe2 O3 , α00 -Fe16 Nx Z2−x , and
seta-potential protein or drug MS (15 kOe) =
20 nm) α0 -Fe8 Nx Z1−x , by wet
delivery) 182.7 emu/g;
ball milling
MR = 45 emu/g)
Chitosan (Cs), 99–120 mg SIL/g
Drug delivery,
with/without silica; Cytotoxicity tests functionalized MNPs
Fe3 O4 Silymarin (SIL) anticancer, [67]
Cs-f-SiO2 @Fe3 O4 , (MCF-7, MTT assay) (Folin–Ciocalteu
antioxidant,
Cs-f-Fe3 O4 method)
Toxin:
2000-fold
dianthin-epidermal
enhancement in tumor
growth factor Enzymatic Activity,
cell cytotoxicity,
APTES Modification (DiaEGF) or TEM, DLS, DSC, In Targeted tumor
SPION 6.7-fold gain in [68]
(SPION@APTES) endosomal escape Vitro Cytotoxicity, therapy, drug delivery
specificity; steric
enhancers (EEE), Relaxivity
stabilization inhibits
glycosylated
agglomeration
triterpenoids SO1861
Functionalized
graphene oxide
(acylated, G-COCl), Nilotinib 400 mg,
polylactic acid, super paramagnetic
polyvinyl alcohol, particles 0.01 g and
polyethylene glycol, Nilotinib (TasignaTM , total MFGO mass
UV-Vis, FTIR,
and nilotinib (second medication for chronic (0.1 g) were kept
MNPs FT-NMR, VSM, SEM, Drug delivery [69]
layer), sodium myelogenous constant in all
TEM, TGA
alginate, polyethylene leukemia) samples. Faster drug
glycol, poly release at acidic pH 3
(lactic-co-glycolic (24 h) vs. slightly basic
acid), polylactic acid pH 7.4 (48 h).
and nilotinib gel
(third layer)
[166 Ho] Fe3 O4 @Au
NPs (150 nm)
conjugated with Tmab
SPIONs, 166 Ho doped Monoclonal antibody TEM, TGA, Multimodal cancer
Au layer coating targets HER2+ [70]
iron oxide trastuzumab (Tmab) cytotoxicity studies therapy
receptors. Cytotoxic
effect toward SKOV-3
ovarian cancer cells.
hydrogen bonding
Silica coating, a between the surface
multistep bonded
synthesis, activated carbohydrate and
NP couples a TLC (thin-layer nucleic acid targets
triethylene glycol chromatography), (NpFeSiIm-
MNPs (Fe2 O3 , ~15 nm, spaced glycosyl ATR FTIR, TG-DTA, Nucleic acid (NA) Sugar/DNA complex)
– [71]
29 emu/g) imidazole; silyl TEM, SEM, EDX, XRD, extraction to ensure nucleic acid
propyl-H-imidazole VSM, BET, 1 H and 13 C selectivity and avoid
functionalization, NMR protein contamination.
glycosylation and high DNA particle
deacetylation to loading ratio of
NpFeSiImSugar NPs. 30–45 wt%
(MNP/DNA ratio)
Hydrodynamic size
(Z-Average),
polydispersity index
(PDI), zeta potential at
pH 7.3,
Caffeic acid volumetric Caf-BSA-SPIONs;
(Caf-SPIONs); Bovine serum albumin susceptibility, and iron tested against A375M
SPIONs Anticancer [72]
citrate-stabilized (BSA) content Atomic melanoma cells,
(Cit-SPION) Emission fibroblasts;
Spectroscopy (AES);
HPLC-UV;
fluorescence; magnetic
field simulations
(COMSOL)
Coatings 2023, 13, 1772 19 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
Monitoring of
Glycyrrhizin pancreatic islets and
(anti-inflammatory, mesenchymal stem
anti-ulcer, cell (MSC) spheroids;
Glycyrrhizin-chitosan
anti-allergic, MRI, inhibition of
SPION (“SPIO”) coating Anti–inflammatory [73]
antioxidant, immunofluorescence inflammatory
(SPIO@Chitosan-GL)
anti-tumor, damage-associated
anti-diabetic, molecular pattern
hepatoprotective) (DAMP) protein in
mice
Silica-coating,
TEM, XRD, XRD
Polyamide 6 (PA6) by
(small/wide angle,
in situ polymerization, Self-healable Multiferroic-
SAXS/WAXS), DSC,
Fe3 O4 MNP to yield self-healable – polymer polyamide 6 (PA6) [74]
magnetic properties
magnetic nanoparticle nanocomposites nanocomposite
(SQUID, 100 K, 400 K),
polymer (SHMNP)
ZFC-FC
composite
Biomedical
Stimuli-responsive
Polylactic applications
hematite (α-Fe2 O3 ) – FTIR, TGA, DSC, VSM PLA/α-Fe2 O3 [75]
acid (PLA) (3D printing,
nanocomposites
cardiovascular stents)
MNP-CA-PEI
nanoparticles
DLS, TGA, SQUID, Nucleic acid delivery
290.74 ± 63.84 nm:
FTIR, zeta-potential, by caveolae-mediated
citric acid Multifunctional
-(GFP plasmid; surface endocytosis;
(CA)-modified MNP magnetic nanocarriers
MNPs MNP/nucleic acid characterization adsorption isotherm [76]
cross-linked with (siRNA, shRNA), gene
polyplexes) (Langmuir, follows pseudo-first
polyethyleneimine delivery
Freundlich), order kinetics; HEK
(PEI)
fluorescence 293 cells were used.
(carbonyldiimidazole
as the crosslinker)
Nanoflower-like or
In situ reduction of Ag nanodumbbell
with gallic acid Antibacterial, (NP/gallic acid ratio
Fe3 O4 –Ag – FE-SEM, FTIR [77]
(reducing agent), silica antitumor of 10:1)
shell multifunctional
nanocomposites
Hyaluronic acid (HA,
ligand for CD44) and
Tested on
antibodies (Abs)
SPIONPs (10 nm, rhabdomyosarcoma
against CD221
toluene), cubosomes. Helenalin Cryo-EM, SAXS, Anticancer cells (RMS) and [78]
coupled to cubosomes
CD44 and CD221) control (fibroblast)
via electrostatic
cells
attraction and
thiol-Michael reaction
Core–shell
magnetoelectric NPs
Surface XRD, HRSEM,
CoFe2 O4 @BaTiO3 obtained as nanorods;
functionalization with HRTEM, SAED, MH Drug delivery; cancer
(CFO@BTO), by Doxorubicin (DOX) 98% drug release in
amphiphilic polymer, measurements, treatment, suitable for
solvothermal and methotrexate 20 min (MF = 4 mT). [79]
polyisobutylene-alt- ZFC–FC, chemo-resistant
synthesis (38 nm, (MTX) Tested on HepG2 and
maleic DLS < zeta-potential, cancers
MS = 47.4 emu/g) HT144 cells and 3D
anhydride (PMA) drug release kinetics
spheroid models
(p < 0.05).
Ellipsoidal shape,
~14 nm. Cellular
Thiolated
response dependent
β-cyclodextrin Doxorubicin (DOX), to XPS, drug release
(Targeted) cancer on IONPs’
IONPs (β-CD-SH), through yield (modelled by [80]
treatment functionalization.
Fe–S bonding DOX-TβCD-IONPs Higuchi model)
Tested against breast
(TβCD-IONPs)
cancer cell line
MCF-07.
Biomedical In vivo models
applications; drug showed increased iron
XRD, TEM, magnetic delivery, imaging content in liver. No
MNP (Fe3 O4 ) Citrate coating – [81]
measurements (VSM) diagnostic (especially viability issues against
in liver, where iron different cell lines
accumulates) (HaCaT and HepG2).
Hybrid nanoparticle
3-aminopropyl-
Luminescent, LMNPs system
triethoxysilane XRD, FTIR, PL, TEM,
Fe3 O4 @BaMoO4 :Eu3+ Triazole derivatives Drug carrier LMNPs@APES-CD [82]
(APTES). VSM
(LMNPs) had high drug loading
β-cyclodextrin (β-CD)
of 61.69 mg/g
Coatings 2023, 13, 1772 20 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
STEM, ICP-MS/MS,
Polyethyleneimine, Fe3 O4 @PEI MNPs
UV-Vis, TGA, FTIR,
Fe3 O4 gold, silica, and dsDNA DNA isolation adsorbed DNA [83]
charge (ζ-potential).
graphene derivatives efficiently
ICP-MS/MS
Efficient thrombolysis
SEM, TEM, XRD, EDX, Thrombolytic
Fe3 O4 –COOH coating rtPA (rabbit carotid artery [84]
VSM, FTIR nanomedicine
occlusion model)
Polymeric matrix of MB@NAV has high
poly(lactic-co-glycolic) MS (higher than
acid (PLGA), commercial NAV
Magnetic beads (MBs),
generating polymeric Affinity protein formulation).
Znx Fe3−x O4
MBs that were neutravidin (NAV), by TEM, HRTEM, DLS, Biosensing (detection Alzheimer’s disease
nanoparticles [85]
covered with glutaraldehyde XRD, FTIR, ICP-MS of Tau protein) biomarker (Tau
(ZnFeNPs), 13 ± 3 nm,
polyethyleneimine crosslinking protein) could be
MS = 81 emu/g
(PEI) (MB@PEI), detected using
obtaining particles of MB@NAV at very low
96 ± 16 nm 63 mg/mL
didodecyldimethy-
XRD, FT-IR
lammonium bromide
Silica, double-chain TG, TEM. liquid
Epirubicin Analytical extraction was the most effective
Fe3 O4 surfactant, ionic chromatography– [86]
hydrochloride (EPI) methods surfactant for
liquids (ILs) fluorescence detection
adsorption tests
(LC-FL)
on MNPs
Fe2+ substitution by
Ni2+ , inverse spinel
Cancer treatment structure;
Nix Fe3−x O4 NPs
XRD, Raman, EDX, (MCF7 and HeLa cell hydrodynamic radii
(x = 0.0, 0.2, 0.4, 0.6, Aminosilane coating – [87]
FTIR, DLS lines); drug delivery, 10 nm (DLS). Coating
0.8, and 1.0)
hyperthermia decreases
agglomeration and
cell viability
Novel encapsulation
Oleic acid (OA) and Biological
Dexamethasone NMR, HR-MS, TEM, system based on
IONPs tetraethylene glycol applications, drug [88]
(Dexa) DLS, HPLC, triazole-derived
(TEG) delivery
micelle precursor
Hyperbranched
biocompatibility
polyglycerol and Drug delivery,
toward normal cells
carboxymethyl IR, NMR, TG, VSM, anticancer, contrast
(HEK-293), high
MNP (Fe3 O4 ) cellulose, to Doxorubicin (DOX) XRD, DLS, HR-TEM agent in magnetic [89]
toxicity against
Fe3 O4 @PG and and UV–Vis resonance
cancerous cells
Fe3 O4 @PG/CMC- imaging MRI
(HeLa).
PEG@DOX
SPIONS
1 (SPION@PGlCLCys)
Copolyester, poly H NMR, Gel
enable further
(globalide-co-ε- Permeation
Enzymatic release, conjugation with
caprolactone) (PGlCL), Methotrexate (MTX); Chromatography
antitumor active biomolecules;
modified with amino conjugation achieved (GPC), HPLC, FTIR,
SPIONs (Fe3 O4 ) nanoplatform (tested drug loaded [90]
acid cysteine (Cys) via via -NH2 group of DSC, TEM/SAED,
on tumor cells SPION@PGlCLCys_MTX
a thiol-ene reaction cysteine XRD, magnetic
MDA-MB 231) obtained by
(PGlCLCys); folic acid properties (VSM),
carbodiimide-
(FA) TGA, DLS
mediated coupling
(amide bond)
DLS, TEM, FTIR, XRD,
MNPs of 8 nm, 12 nm
Oleic acid, allyl amine VSM, TGA,
and 16 nm prepared
(synthesis), Calorimetric magnetic Hyperthermia, Cancer
by seed-mediated
polypropylene DOX and CUR loaded fluid hyperthermia, treatment (tested on
Fe, MnFe, CoFe method from [91]
sulphide PPS-coating PPS–MNPs UV-Vis (drug human epithelial cells
M-acetylacetonates;
to produce PPS-MNPs encapsulation HEK293)
high breast cancer cell
(80 ± 15 nm) efficiency), drug
death (95%)
loading (HPLC)
3-amino propyl
FT-IR, SEM, EDX,
triethoxy silane
TEM, XRD, VSM, Effect studied on
(APTES) coating to
MNP (Fe3 O4 ) Doxorubicin (Dox) TGA, and zeta Anti-cancer MCF7 human breast [92]
MNPs@SiO2 /CMT
potential, fluorescence cancer cells
(carboxymethyl
microscopy
tragacanth)
Coatings 2023, 13, 1772 21 of 31

Table 4. Cont.

Characterization
NP Type Coating Agent Active Agent Activity Obs. Ref.
Methods
FTIR, AFM, SEM,
agarose gel Fe3 O4 @PDA@PEI
Dopamine (DA), electrophoresis, Gene vector (DNA modified NPs are
Fe3 O4 PEI-modified [93]
self-polymerized fluorescence delivery) stable hydrophilic
microscopy, flow NPs (50–150 nm)
cytometry
Superparamagnetic
DLS, zeta potential,
behavior useful for
NMR, IR, magnetism Biomedical
magnetic
MNPs (iron oxide, Mesoporous silica trans-resveratrol (SQUID, ZFC-FC), (protein–ligand,
bioseparation; high [94]
18 nm diameter) shell (93 nm diameter) (post-silanization) fluorescence immunoassay
zeta-potential kept the
resonance energy design)
mesoporous NPs in
transfer (FRET)
alkaline solution
High DOX loading:
DLS, ζ-potential, 732 µg/mg
magnetic Anticancer; drug
FTIR, TEM, drug (DOX/MNC) and
nanocomposites Oleic-acid-modified, delivery (against A549
Doxorubicin (Dox) loading/release 943 µg/mg [95]
(MNCs), nanocapsules Nylon-6 coated and HEK 293FT cell
(UV-Vis), cytotoxicity (DOX/NC);
(NCs) based on Fe3 O4 lines)
studies pH-sensitive drug
release
Anticancer,
In situ solvothermal
Stabilizers: 3,4- hyperthermia (human
process of
dihydroxybenzhydrazide normal dermal
TEM, XPS, FTIR, VSM MNPs-magnetite
Fe3 O4 nanoclusters (DHBH) and poly [3,4- – fibroblasts-BJ, colon [96]
(magnetization) nanoclusters, MNC of
dihydroxybenzhydrazide] adenocarcinoma-
50 emu/g and
(PDHBH) CACO2, and
60 emu/g
melanoma-A375)
Cobalt-Iron Ferrite MTT assay on
Nanoparticles Surface modification Cytocompatibility, fibroblast cells
Cox Fe1−x Fe2 O4 with amino-silane – SEM, EDX, XRD, FTIR biomedical (cytotoxicity tests); [97]
(x = 0.0, 0.2,0.4, 0.6, 0.8, (AEPTMS) applications Co/Fe ratio influences
and 1.0) cytotoxicity
Fe3 O4 -L-Cys-Dox NPs
showed
EDS, SAED, XRD,
Drug delivery, anti-melanoma
L-Cysteine FTIR, TEM. XPS,
Fe3 O4 Doxorubicin (Dox) anticancer activity on mouse [98]
(L-Cys)-coating Mössbauer
(anti-melanoma) (B16F10) and human
spectroscopy, SQUID
(A375) metastatic
melanoma

Various MNP systems have been designed to overcome embolism caused by these
nanoparticles, which requires coating with biocompatible and non-cytotoxic polymers,
such as poly (globalideco-ε-caprolactone) (PGlCL), modified with the amino acid cysteine
(Cys) via a thiol-ene reaction (PGlCLCys) [90]. The reaction scheme utilized to produce
a coating of SPIONS (SPION@PGlCLCys) and further conjugation with folic acid (FA) or
the anti-cancer drug methotrexate (MTX) is described in Figure 6. Cysteine (Cys) was
chosen specifically due to its good compatibility with SPIONs, which it binds to through
carboxylic and thiol groups, while the selection of biomolecules (FA, MTX) was aimed
at anticancer treatment, as experiments showed a 45% release of MTX within 72 h under
enzymatic-triggered release and a reasonable reduction in tumor cell (breast carcinoma
MDA-MB 231) viability of 20%. The tumoral cell viability remains high, although the MTX
loading wss quite low at 3.20 µg MTX/mg IONP [90].
The use of surface-functionalized magnetic nanoparticles (MNPs) in medical ther-
apies shows great promise, but it is important to be aware of potential side effects and
complications related to biocompatibility and toxicity, accumulation and biodistribution,
retention and clearance, inflammatory/allergic response, potential interference, agglom-
eration, under/overdosing, unintended effect on nearby tissues/organs, rare element
toxicity (present in some surface coatings), incomplete drug release, clinical translation,
and regulatory approval.
Coatings 2023,
Coatings 13, 13,
2023, 17721772 22 36
26 of of 31

Figure6. 6.
Figure (A)(A) Synthesis
Synthesis of PGICLCys
of PGICLCys and SPIONs
and SPIONs and conjugation
and conjugation with folicwith
acidfolic acid
(FA) or (FA) or
methotrexate
methotrexate
(MTX). (MTX). SPION@PGlCLCys_MTX:
SPION@PGlCLCys_MTX: (B) drug delivery (B) drug
assaydelivery assaypH
at lysosomal at lysosomal pH or
(pH 5.3) with (pH 5.3)
without
with or without protease (ENZ); (C) breast carcinoma-derived MDA-MB 231 cells viability after 72
protease (ENZ); (C) breast carcinoma-derived MDA-MB 231 cells viability after 72 h at different MTX
h at different MTX concentrations. Reprinted under the terms and conditions of the Creative Com-
concentrations.
mons AttributionReprinted
(CC BY) under
license the
fromterms and conditions of the Creative Commons Attribution
ref. [90].
(CC BY) license from ref. [90].
The use of surface-functionalized magnetic nanoparticles (MNPs) in medical thera-
piesMagnetization of the magnetic
shows great promise, but it iscore is highly
important to important,
be aware ofaspotential
it furtherside
dictates theand
effects final
behavior of the magnetic
complications related to nanoplatform
biocompatibilitywhen and subjected to a magnetic and
toxicity, accumulation [Link],
It is noteworthy
that other compounds such as nitrides γ 0 -Fe N, through a consecutive reduction and
4
retention and clearance, inflammatory/allergic response, potential interference, agglom-
nitridation strategy, have gained
eration, under/overdosing, research
unintended effectmomentum due to their superior
on nearby tissues/organs, rare elementmagnetic
tox-
properties when compared to typical IONPs (Figure 7) [66]. Such a new
icity (present in some surface coatings), incomplete drug release, clinical translation, and magnetic core
(M = 182.7 emu/g for γ 0 -Fe N) could yield novel high-performance magnetic nanoplatforms.
S
regulatory approval. 4
Depending on the
Magnetization composition
of the and is
magnetic core surface
highlyfunctionalization, MNPs
important, as it further may have
dictates differ-
the final
ent levels of biocompatibility, and some coatings or functional groups may
behavior of the magnetic nanoplatform when subjected to a magnetic field. It is notewor- induce toxicity
orthy
provoke an immune
that other compounds response.
such asTherefore,
nitrides γ′-Fethorough biocompatibility
4N, through a consecutivetesting
reductionis crucial.
and
Moreover,
nitridationMNPs canhave
strategy, accumulate in various
gained research tissues and
momentum organs,
due to theirespecially
superior in the liver,
magnetic
spleen, and lymph nodes. Understanding and controlling their biodistribution is important
in order to prevent potential long-term effects. The long-term retention of MNPs in the
Coatings 2023, 13, 1772 23 of 31

body, especially in critical organs, could lead to complications, so ensuring efficient clear-
ance mechanisms is essential to mitigate potential risks. Some surface coatings may trigger
inflammatory responses, which can lead to local or systemic reactions, potentially causing
discomfort or more serious complications. Also, allergic reactions may occur within some
individuals, ranging from mild skin irritation to severe anaphylactic responses. While some
degree of interference can occur with other medical devices or implants, a more serious
issue is related to the fate of the MNPs in the biological system. In targeted drug delivery,
there is a risk of unintentional effects on neighboring healthy tissues if the targeting mecha-
nisms are not sufficiently specific. These effects can be exacerbated by agglomeration of
NPs, a phenomenon which occurs based on specific microenvironments and could lead
to embolisms or blockages in blood vessels. A careful evaluation of the release profiles to
ensure the correct dosage and distribution of MNPs is crucial: overdosing leads to toxicity,
Coatings 2023, 13, 1772 27 of 36
while underdosing results in ineffective therapy. In drug delivery applications, there may
be challenges in achieving precise control over drug release rates, and this could lead
to suboptimal therapeutic outcomes. In all cases, surface-functionalized MNPs have to
properties
meet when standards
regulatory compared for
to typical
clinicalIONPs (Figureand
translation, 7) [66].
this Such a new
involves magnetic
rigorous core and
testing (MS
= 182.7 emu/g
approval for γ′-Fe4N) could yield novel high-performance magnetic nanoplatforms.
processes.

Figure 7. (A) Space-filling models of γ-Fe2O3, Fe, and γ′-Fe4N crystal structure transitions from the
Figure 7. (A) Space-filling models of γ-Fe2 O3 , Fe, and γ0 -Fe4 N crystal structure transitions from the
reduction and nitridation steps; (B) XRD patterns of γ-Fe2O3 and the synthesized γ′-Fe 0
4N nanopar-
reduction
ticles; (C) and nitridation
static magneticsteps; (B) XRD
hysteresis patterns
loops of2O
of γ-Fe γ-Fe 2 O3the
3 and
andsynthesized
the synthesized
γ′-Feγ4N-Fe4 N nanopar-
nanoparticles
ticles; (C) static magnetic hysteresis 0
measured by PPMS with the external loops of γ-Fe
magnetic field2 O3 andfrom
swept the synthesized γ -Fe
−15 to +15 kOe. 4 Ninset
The nanoparticles
figure (D)
measured by PPMS
shows hysteresis with
loops the external
within magnetic
a field range of ±2field
[Link] −15 permission
fromwith
Reprinted to +15 [Link]
The ACS.
inset figure
(D) shows hysteresis loops within a field range of ±2 kOe. Reprinted with permission from ACS.
Depending on the composition and surface functionalization, MNPs may have dif-
It is important
ferent levels to note that rigorous
of biocompatibility, and somepre-clinical
coatings ortesting and groups
functional comprehensive
may induce risktox-
as-
sessments are essential steps in the development and application of surface-functionalized
icity or provoke an immune response. Therefore, thorough biocompatibility testing is cru-
MNPs in medical
cial. Moreover, MNPstherapies. Additionally,
can accumulate closetissues
in various monitoring of patients
and organs, receiving
especially in theMNP-
liver,
based therapies is crucial in order to promptly identify and address any
spleen, and lymph nodes. Understanding and controlling their biodistribution potential side effects
is im-
or complications. Surface functionalization [99] has propelled MNPs into the forefront of
portant in order to prevent potential long-term effects. The long-term retention of MNPs
drug delivery, redefining therapeutic precision. Rigorous characterization techniques, cou-
in the body, especially in critical organs, could lead to complications, so ensuring efficient
clearance mechanisms is essential to mitigate potential risks. Some surface coatings may
trigger inflammatory responses, which can lead to local or systemic reactions, potentially
causing discomfort or more serious complications. Also, allergic reactions may occur
within some individuals, ranging from mild skin irritation to severe anaphylactic re-
Coatings 2023, 13, 1772 24 of 31

pled with in vitro and in vivo validation studies, underscore the transformative potential
of surface-engineered MNPs in revolutionizing drug delivery paradigms, offering novel
avenues for personalized and targeted therapies [100].

6. Challenges and Future Perspectives

While remarkable strides have been made in the surface functionalization of magnetic
nanoparticles (MNPs), several challenges and promising avenues lie ahead. This section
delves into the intricacies of these challenges and outlines future directions that hold the
potential to reshape the field. Some of the most stringent aspects that require further
improvements have been highlighted in Figure 8, and they include: biocompatibility and
toxicity, long-term stability, seamless and time-effective clinical translation, qualitative and
Coatings 2023, 13, 1772 quantitative control, multifunctionality, a deeper understanding of the structure–function
29 of 36
relationship, enhanced in vivo behavior and targeting precision, multimodal integration,
and exploring other areas of interest beyond biomedicine.

Figure 8. The main

main parameters
parameters and
andfeatures
featuresthat
thatneed
needtotobebeaddressed
addressedbyby future
future MNP
MNP nanoplat-
nanoplatforms
forms for efficient use in biomedical applications and
for efficient use in biomedical applications and beyond. beyond.

TheMNPs’
As demand for multifunctional
prevalence in biomedicalMNPs with multiple
applications surface
increases functionalities
[101], adds
ensuring their bio-
complexity. Balancing diverse functionalities while maintaining stability and
compatibility and minimizing potential toxicity remains a critical challenge. Therefore, avoiding in-
terference biocompatibility
thorough requires innovative design strategies
assessments and
(in vitro comprehensive
and in vivo studies)characterization.
are imperative. Un- Sur-
raveling the intricate interplay between surface modifications and functional
face modifications that enhance biocompatibility, such as PEGylation, must be balanced outcomes is
a continual
with potentialchallenge. Advanced
alterations computational
in surface methods,
functionality. coupled the
Maintaining withstability
detailedofexperi-
surface-
mental studies, MNPs
functionalized are essential to deciphering
over extended periodstheiscomplex
vital forstructure–function relationships.
their efficacy. Challenges such as
Achieving
ligand precise targeting
detachment, of MNPs
aggregation, to specific cells
or degradation needortotissues remainsthrough
be addressed a challenge,
robustpar-
coat-
ticularly
ing in dynamic
strategies biological
and long-term environments.
stability Incorporating responsive
studies. Multi-parametric elements
characterization into
techniques
MNPs’
can shedcoatings
light onthat enableissues.
stability active targeting upon specific stimuli could enhance targeting
precision [38].
While surface-functionalized MNPs show great promise in preclinical studies, their
Elucidating
seamless the behavior
translation of surface-functionalized
into clinical MNPs in
settings poses significant complex biological
challenges. Rigorousenvi-
safety
ronments is crucial. Studying factors like protein corona formation, biodistribution, and
clearance pathways will provide insights into their fate after administration inside the
human body [10]. In nanotechnology, the protein corona plays a key role in dictating the
biological fate and functionality of these nanoscale entities; when nanoparticles, including
magnetic nanoparticles (MNPs), come into contact with biological fluids, such as blood or
Coatings 2023, 13, 1772 25 of 31

assessments, scalability of production, and regulatory approvals are crucial hurdles that
need to be overcome for clinical applications. Achieving precise quantitative control over
surface functionalization remains a challenge. Determining the exact number of functional
moieties per MNP requires advanced analytical techniques. Techniques like single-particle
tracking or advanced spectroscopic methods may offer new insights.
The demand for multifunctional MNPs with multiple surface functionalities adds
complexity. Balancing diverse functionalities while maintaining stability and avoiding
interference requires innovative design strategies and comprehensive characterization.
Unraveling the intricate interplay between surface modifications and functional outcomes
is a continual challenge. Advanced computational methods, coupled with detailed experi-
mental studies, are essential to deciphering the complex structure–function relationships.
Achieving precise targeting of MNPs to specific cells or tissues remains a challenge, par-
ticularly in dynamic biological environments. Incorporating responsive elements into
MNPs’ coatings that enable active targeting upon specific stimuli could enhance targeting
precision [38].
Elucidating the behavior of surface-functionalized MNPs in complex biological envi-
ronments is crucial. Studying factors like protein corona formation, biodistribution, and
clearance pathways will provide insights into their fate after administration inside the
human body [10]. In nanotechnology, the protein corona plays a key role in dictating the
biological fate and functionality of these nanoscale entities; when nanoparticles, including
magnetic nanoparticles (MNPs), come into contact with biological fluids, such as blood
or interstitial fluid, they instantaneously interact with a plethora of biomolecules such
as proteins present in these environments. Upon exposure to biological fluids, proteins
rapidly and spontaneously adsorb onto the surface of the nanoparticles, forming a dynamic
and complex layer, often referred to as the protein corona, a complex phenomenon influ-
enced by factors like nanoparticle size, shape, surface charge, and surface chemistry. The
protein corona, in turn, fundamentally alters the biological identity of the nanoparticle by
mediating interactions with cells, influencing cellular uptake, intracellular trafficking, and
biological responses, and determines the fate of the nanoparticle within the body, impacting
aspects such as circulation time, distribution in tissues, and potential clearance mechanisms.
The concept of protein corona formation represents a dynamic and intricate phenomenon
at the interface of nanoparticles and biological systems, with profound influence over the
biological behavior and fate of nanoparticles in vivo, underscoring its critical importance
in the field of nanomedicine. Researchers are actively working to unravel the complexities
of protein corona dynamics to engineer nanoparticles with enhanced biocompatibility and
therapeutic efficacy. Iron oxides, for instance, have been shown to remap the immunologi-
cal tumor environment, especially when interacting with macrophage response through
polarization and reprogramming [102].
A closer look at the commercial solutions offered on the market today highlights the
presence of quite a few suppliers, such as Dynabeads (Thermo Fisher Scientific, Waltham,
MA, USA), Micromod Partikeltechnologie GmbH, NanoMAG-D (Macherey-Nagel, Düren,
Germany), Ocean NanoTech MagVigen™ Magnetic Nanoparticles (Ocean NanoTech,
San Diego, CA, USA), Bangs Laboratories Magnetic Microspheres (Bangs Laboratories, Inc.,
Fishers, IN, USA), Ademtech Functionalized Magnetic Particles (Ademtech, Pessac, France),
NanoXact (NanoComposix, San Diego, CA, USA), and MagSi Beads (Chemicell, Berlin,
Germany). To get a more in-depth estimation of the costs and actual surface coverings
offered by one of the mentioned brands, a brief analysis of Micromod’s listings shows that
10 mL of MNPs (300 nm; 10 mg/mL) costs just shy of EUR 250, and various functionaliza-
tions are possible (dextran, silicate, etc). The cost, however, remains prohibitive, especially
when related to NPs’ dry weight content. There are quite a few companies (including
major brands) offering commercial solutions, many of which can be further tailored to suit
demand for specific properties, coatings, concentrations, etc. Each additional request raises
the overall price. Therefore, tailoring magnetic formulations for specific applications could
be conducted in-house instead, as this approach costs a lot less than commercial solutions
Coatings 2023, 13, 1772 26 of 31

and represents one of the key benefits of synthesizing MNPs in-house rather than through
procurement services. A brief comparison correlating some of the recent advances in the
field of surface-functionalized magnetic nanoparticles (MNPs) with solutions available on
the market is given in Table 5.

Table 5. Short comparison correlating commercial solutions available today on the market to the
recent advances and the current state-of-the-art.

Application Recent Advances Market Solutions

Established strategies like silane coupling
Advanced strategies like click chemistry, agents and antibody immobilization;
Surface Functionalization Strategies polymer brushes via ATRP, advanced strategies emerging in
multifunctional coatings. commercial products, like click
chemistry-based functionalization kits.
MNPs functionalized with specific ligands
Novel surface coatings and functional
for targeted drug delivery. Some
Applications in Drug Delivery groups—enhanced drug loading,
companies provide customizable options
controlled release.
for specific drug payloads.
High-quality coatings, ensuring stability
Coatings with superior magnetic properties
and improved imaging performance; some
Magnetic Resonance Imaging (MRI) and responsive materials for improved
products integrate advanced surface
contrast in MRI.
modifications to enhance contrast.
Commercial options with tailored surface
Surface functionalization strategies to
properties to achieve precise heating of
Hyperthermia Treatment optimize heating efficiency for
targeted tissues within physiologically
hyperthermia applications.
relevant limits.
Surface functionalizations optimized for
Improved diagnostic capabilities through
specific diagnostic assays, that may include
Diagnostic Applications enhanced binding specificity and
pre-conjugated antibodies or customizable
signal amplification.
options for specific biomarker detection.
Multifunctional MNPs that combine
Recent research focuses on integrating
features like drug delivery, imaging, and
Multifunctionality multiple functionalities within a single
targeting within a single particle, designed
NP platform.
to streamline complex applications.
An emerging interest in functionalized
Environmental Remediation Functionalized MNPs are being explored in MNPs for non-biomedical uses, with
and Catalysis catalysis and environmental remediation. customizable options for research in
these fields.

Integrating multiple functionalities into a single MNP, such as combining imaging

and therapy, is a complex challenge aimed at the theranostics realm. Developing stream-
lined strategies for co-functionalization while preserving each functionality’s integrity
is an ongoing pursuit. Finally, exploring novel applications of surface-functionalized
MNPs beyond biomedicine, such as environmental remediation, catalysis, and energy
storage, offers exciting future prospects. Tailoring surface functionalization for non-
biomedical contexts requires creative adaptations and a comprehensive understanding of
each application’s requirements.
Looking forward, the field of surface functionalization of MNPs holds immense potential.
Addressing these challenges requires interdisciplinary collaboration, innovative engineering,
and meticulous characterization. As the complexities are unraveled, surface-engineered
MNPs are poised to continue transforming diverse domains, offering solutions to some of
the most pressing challenges in science, technology, and medicine [20,21,103–105].
Coatings 2023, 13, 1772 27 of 31

7. Conclusions
The journey through recent advances in the surface functionalization of magnetic
nanoparticles (MNPs) has revealed a captivating landscape where scientific innovation con-
verges with transformative applications. The remarkable synergy between nanotechnology
and surface engineering has ushered in a new era, unlocking the full potential of MNPs
across diverse domains. Surface functionalization has redefined the capabilities of MNPs in
multimodal imaging, drug delivery, and catalysis. The strategic tailoring of MNP surfaces
has propelled multimodal imaging, enhancing contrast, enabling targeted imaging, and
fostering the integration of different imaging modalities. This convergence has profound
implications in disease diagnosis, therapeutic monitoring, and understanding complex
biological processes. The horizon of the surface functionalization of MNPs gleams with pos-
sibilities. From fine-tuning imaging contrast to precise drug delivery, surface-engineered
MNPs stand as catalysts of transformation. Collaboration between disciplines, synergy
between theory and experiment, and unwavering commitment to innovation will rewrite
the boundaries of what is possible.

Funding: This work was supported by the Romanian Ministry of Research and Innovation through
Project No. PN-III-P1-1.1-TE-2021-1657 (TE 84/2022), TE 91/2022 and by the Core Program of the
National Institute of Materials Physics, granted by the Romanian Ministry of Research, Innovation
and Digitization through the Project PC1-PN23080101.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: This work is funded by the Core Program of the National Institute of Materials
Physics, granted by the Romanian Ministry of Research, Innovation and Digitalization through the
Project PC1-PN23080101 and Projects No. PN-III-P1-1.1-TE-2021-1657 (TE 84/2022) and TE 91/2022.
Conflicts of Interest: The author declares no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.

References
1. Jiang, K.Y.; Zhang, L.L.; Bao, G. Magnetic iron oxide nanoparticles for biomedical applications. Curr. Opin. Biomed. Eng. 2021,
20, 100330. [CrossRef] [PubMed]
2. Shankar, M.; Kesavan, S.S.; Biswas, K. Exploring the Potentials of Magnetic Nanoscale Material for Different Biomedical
Applications: A Review. Bionanoscience 2023. [CrossRef]
3. Matveeva, V.G.; Bronstein, L.M. Magnetic Nanoparticle-Containing Supports as Carriers of Immobilized Enzymes: Key Factors
Influencing the Biocatalyst Performance. Nanomaterials 2021, 11, 2257. [CrossRef] [PubMed]
4. Palade, P.; Comanescu, C.; Radu, C. Synthesis of Nickel and Cobalt Ferrite-Doped Graphene as Efficient Catalysts for Improving
the Hydrogen Storage Kinetics of Lithium Borohydride. Materials 2023, 16, 427. [CrossRef]
5. Mehak; Thummer, R.P.; Pandey, L.M. Surface modified iron-oxide based engineered nanomaterials for hyperthermia therapy of
cancer cells. Biotechnol. Genet. 2023. [CrossRef]
6. Pryazhnikov, D.V.; Kubrakova, I.V. Surface-Modified Magnetic Nanoscale Materials: Preparation and Study of Their Structure,
Composition, and Properties. J. Anal. Chem. 2021, 76, 685–706. [CrossRef]
7. Ansari, M.J.; Kadhim, M.M.; Hussein, B.A.; Lafta, H.A.; Kianfar, E. Synthesis and Stability of Magnetic Nanoparticles. Bio-
nanoscience 2022, 12, 627–638. [CrossRef]
8. Siddique, S.; Chow, J.C.L. Recent Advances in Functionalized Nanoparticles in Cancer Theranostics. Nanomaterials 2022, 12, 2826.
[CrossRef]
9. Comanescu, C. Magnetic Nanoparticles: Current Advances in Nanomedicine, Drug Delivery and MRI. Chemistry 2022, 4, 872–930.
[CrossRef]
10. Senthilkumar, N.; Sharma, P.K.; Sood, N.; Bhalla, N. Designing magnetic nanoparticles for in vivo applications and understanding
their fate inside human body. Coordin. Chem. Rev. 2021, 445, 214082. [CrossRef]
11. Liu, Y.K.; Su, G.M.Y.; Zhang, R.Y.; Dai, R.J.; Li, Z. Nanomaterials-Functionalized Hydrogels for the Treatment of Cutaneous
Wounds. Int. J. Mol. Sci. 2023, 24, 336. [CrossRef] [PubMed]
12. Gambhir, R.P.; Rohiwal, S.S.; Tiwari, A.P. Multifunctional surface functionalized magnetic iron oxide nanoparticles for biomedical
applications: A review. Appl. Surf. Sci. Adv. 2022, 11, 100303. [CrossRef]
Coatings 2023, 13, 1772 28 of 31

13. Gwon, H.; Park, S.; Lu, Q.; Choi, H.J.; Lee, S. Size effect of iron oxide nanorods with controlled aspect ratio on magneto-responsive
behavior. J. Ind. Eng. Chem. 2023, 124, 279–286. [CrossRef]
14. Jimenez-Carretero, M.; Rodriguez-Lopez, J.; Ropero-Moreno, C.; Granada, J.; Delgado-Martin, J.; Martinez-Bueno, M.; Fernandez-
Vivas, A.; Jimenez-Lopez, C. Biomimetic magnetic nanoparticles for bacterial magnetic concentration in liquids and qPCR-
detection. Food Control 2023, 147, 109623. [CrossRef]
15. Franzel, L.; Bertino, M.F.; Huba, Z.J.; Carpenter, E.E. Synthesis of magnetic nanoparticles by pulsed laser ablation. Appl. Surf. Sci.
2012, 261, 332–336. [CrossRef]
16. Liu, J.; Su, D.; Wu, K.; Wang, J.P. High-moment magnetic nanoparticles. J. Nanopart. Res. 2020, 22, 66. [CrossRef]
17. Carvallo, C.; Fondet, A.; Le Fèvre, R.; Taverna, D.; Guyodo, Y.; Chebbi, I.; Dupuis, V.; Lagroix, F.; Khelfallah, M.; Guigner, J.-M.;
et al. Magnetic and structural properties of biogenic magnetic nanoparticles along their production process for use in magnetic
hyperthermia. J. Magn. Magn. Mater. 2023, 575, 170726. [CrossRef]
18. Iacob, N.; Kuncser, A.; Comanescu, C.; Palade, P.; Kuncser, V. Optimization of magnetic fluid hyperthermia with respect to
nanoparticle shape-related parameters: Case of magnetite ellipsoidal nanoparticles. J. Nanopart. Res. 2020, 22, 138. [CrossRef]
19. Pedroso-Santana, S.; Fleitas-Salazar, N. The Use of Capping Agents in the Stabilization and Functionalization of Metallic
Nanoparticles for Biomedical Applications. Part. Part. Syst. Charact. 2023, 40, 2200146. [CrossRef]
20. Lu, A.H.; Salabas, E.E.; Schüth, F. Magnetic Nanoparticles: Synthesis, Protection, Functionalization, and Application. Angew.
Chem. Int. Ed. 2007, 46, 1222–1244. [CrossRef]
21. Majidi, S.; Zeinali, F.; Samad, S.; Farkhani, M.; Soleymani, M.; Akbarzadeh, A. Current methods for synthesis of magnetic
nanoparticles. Artif. Cells Nanomed. Biotechnol. 2016, 44, 722–734. [CrossRef] [PubMed]
22. Gareev, K.; Tagaeva, R.; Bobkov, D.; Yudintceva, N.; Goncharova, D.; Combs, S.E.; Ten, A.; Samochernych, K.; Shevtsov, M.
Passing of Nanocarriers across the Histohematic Barriers: Current Approaches for Tumor Theranostics. Nanomaterials 2023,
13, 1140. [CrossRef] [PubMed]
23. Hao, H.S.; Chen, Y.; Wu, M.Y. Biomimetic nanomedicine toward personalized disease theranostics. Nano Res. 2021, 14, 2491–2511.
[CrossRef]
24. Palade, P.; Comanescu, C.; Kuncser, A.; Berger, D.; Matei, C.; Iacob, N.; Kuncser, V. Mesoporous Cobalt Ferrite Nanosystems
Obtained by Surfactant-Assisted Hydrothermal Method: Tuning Morpho-structural and Magnetic Properties via pH-Variation.
Nanomaterials 2020, 10, 476. [CrossRef] [PubMed]
25. Aslam, H.; Shukrullah, S.; Naz, M.Y.; Fatima, H.; Hussain, H.; Ullah, S.; Assiri, M.A. Current and future perspectives of
multifunctional magnetic nanoparticles based controlled drug delivery systems. J. Drug Deliv. Sci. Technol. 2022, 67, 102946.
[CrossRef]
26. Hur, J.U.; Shin, J.R.; Han, J.S.; Kim, Y.H.; An, G.S. Self-assembled core-shell Fe3 O4 -Pt nanoparticles via silylation/polymerization-
based amino-functionalization. Colloid Interfac. Sci. 2022, 50, 100655. [CrossRef]
27. Low, L.E.; Lim, H.P.; Ong, Y.S.; Siva, S.P.; Sia, C.S.; Goh, B.H.; Chan, E.S.; Tey, B.T. Stimuli-controllable iron oxide nanoparticle
assemblies: Design, manipulation and bio-applications. J. Control Release 2022, 345, 231–274. [CrossRef]
28. Strassburg, S.; Mayer, K.; Scheibel, T. Functionalization of biopolymer fibers with magnetic nanoparticles. Phys. Sci. Rev. 2022, 7,
1091–1117. [CrossRef]
29. Darroudi, M.; Gholami, M.; Rezayi, M.; Khazaei, M. An overview and bibliometric analysis on the colorectal cancer therapy by
magnetic functionalized nanoparticles for the responsive and targeted drug delivery. J. Nanobiotechnol. 2021, 19, 399. [CrossRef]
30. Mahajan, R.; Suriyanarayanan, S.; Nicholls, I.A. Improved Solvothermal Synthesis of gamma-Fe2 O3 Magnetic Nanoparticles for
SiO2 Coating. Nanomaterials 2021, 11, 1889. [CrossRef]
31. Elahi, N.; Rizwan, M. Progress and prospects of magnetic iron oxide nanoparticles in biomedical applications: A review. Artif.
Organs 2021, 45, 1272–1299. [CrossRef] [PubMed]
32. Ferreira-Faria, I.; Yousefiasl, S.; Macario-Soares, A.; Pereira-Silva, M.; Peixoto, D.; Zafar, H.; Raza, F.; Faneca, H.; Veiga, F.;
Hamblin, M.R.; et al. Stem cell membrane-coated abiotic nanomaterials for biomedical applications. J. Control Release 2022, 351,
174–197. [CrossRef] [PubMed]
33. Das, P.; Jana, N.R. Biomedical Applications of Functional Polyaspartamide-Based Materials. ACS Appl. Polym. Mater. 2021, 3,
4791–4811. [CrossRef]
34. Klekotka, U.; Zambrzycka-Szelewa, E.; Satula, D.; Kalska-Szostko, B. Stability Studies of Magnetite Nanoparticles in Environmen-
tal Solutions. Materials 2021, 14, 5069. [CrossRef] [PubMed]
35. Zakhireh, S.; Barar, J.; Adibkia, K.; Beygi-Khosrowshahi, Y.; Fathi, M.; Omidain, H.; Omidi, Y. Bioactive Chitosan-Based
Organometallic Scaffolds for Tissue Engineering and Regeneration. Topics Curr. Chem. 2022, 380, 13. [CrossRef] [PubMed]
36. Kwizera, E.A.; Stewart, S.; Mahmud, M.M.; He, X.M. Magnetic Nanoparticle-Mediated Heating for Biomedical Applications.
J. Heat Trans.-T Asme 2022, 144, 030801. [CrossRef] [PubMed]
37. Hu, B.; Rotherham, M.; Farrow, N.; Roach, P.; Dobson, J.; El Haj, A.J. Immobilization of Wnt Fragment Peptides on Magnetic
Nanoparticles or Synthetic Surfaces Regulate Wnt Signaling Kinetics. Int. J. Mol. Sci. 2022, 23, 10164. [CrossRef]
38. Mohapatra, A.; Uthaman, S.; Park, I.K. External and Internal Stimuli-Responsive Metallic Nanotherapeutics for Enhanced
Anticancer Therapy. Front. Mol. Biosci. 2021, 7, 597634. [CrossRef]
Coatings 2023, 13, 1772 29 of 31

39. Kothandaraman, H.; Kaliyamoorthy, A.; Rajaram, A.; Kalaiselvan, C.R.; Sahu, N.K.; Govindasamy, P.; Rajaram, M. Functionaliza-
tion and Haemolytic analysis of pure superparamagnetic magnetite nanoparticle for hyperthermia application. J. Biol. Phys. 2022,
48, 383–397. [CrossRef]
40. Duong, H.D.T.; Yoon, S.H.; Nguyen, D.T.; Kim, K.S. Magnetic heating of water dispersible and size-controlled superparamagnetic
cobalt iron oxide nanoparticles. Powder Technol. 2023, 427, 118720. [CrossRef]
41. Ghosal, K.; Chatterjee, S.; Thomas, S.; Roy, P. A Detailed Review on Synthesis, Functionalization, Application, Challenges, and
Current Status of Magnetic Nanoparticles in the Field of Drug Delivery and Gene Delivery System. AAPS PharmSciTech 2022,
24, 25. [CrossRef]
42. Arias-Ramos, N.; Ibarra, L.E.; Serrano-Torres, M.; Yague, B.; Caverzan, M.D.; Chesta, C.A.; Palacios, R.E.; Lopez-Larrubia, P. Iron
Oxide Incorporated Conjugated Polymer Nanoparticles for Simultaneous Use in Magnetic Resonance and Fluorescent Imaging of
Brain Tumors. Pharmaceutics 2021, 13, 1258. [CrossRef]
43. Avarand, S.; Morsali, A.; Heravi, M.M.; Beyramabadi, S.A. A quantum chemical study on the magnetic nanocarrier-tirapazamine
drug delivery system. Nanosyst.-Phys. Chem. M 2021, 12, 167–174. [CrossRef]
44. Beagan, A.M.; Alghamdi, A.A.; Lahmadi, S.S.; Halwani, M.A.; Almeataq, M.S.; Alhazaa, A.N.; Alotaibi, K.M.; Alswieleh, A.M.
Folic Acid-Terminated Poly(2-Diethyl Amino Ethyl Methacrylate) Brush-Gated Magnetic Mesoporous Nanoparticles as a Smart
Drug Delivery System. Polymers 2021, 13, 59. [CrossRef]
45. Valls-Chivas, A.; Gomez, J.; Garcia-Peiro, J.I.; Hornos, F.; Hueso, J.L. Enzyme-Iron Oxide Nanoassemblies: A Review of
Immobilization and Biocatalytic Applications. Catalysts 2023, 13, 980. [CrossRef]
46. Belleti, E.; Bevilaqua, V.R.; Brito, A.M.M.; Modesto, D.A.; Lanfredi, A.J.C.; Viviani, V.R.; Nantes-Cardoso, I.L. Synthesis of
bioluminescent gold nanoparticle-luciferase hybrid systems for technological applications. Photoch. Photobio Sci. 2021, 20,
1439–1453. [CrossRef] [PubMed]
47. Boosz, P.; Pfister, F.; Stein, R.; Friedrich, B.; Fester, L.; Band, J.; Muhlberger, M.; Schreiber, E.; Lyer, S.; Dudziak, D.; et al.
Citrate-Coated Superparamagnetic Iron Oxide Nanoparticles Enable a Stable Non-Spilling Loading of T Cells and Their Magnetic
Accumulation. Cancers 2021, 13, 4143. [CrossRef]
48. Cheah, P.; Qu, J.; Li, Y.; Cao, D.M.; Zhu, X.C.; Zhao, Y.F. The key role of reaction temperature on a polyol synthesis of water-
dispersible iron oxide nanoparticles. J. Magn. Magn. Mater. 2021, 540, 168481. [CrossRef]
49. Correa, T.; Bazylinski, D.A.; Garcia, F.; Abreu, F. A rapid and simple preparation of amphotericin B-loaded bacterial magnetite
nanoparticles. RSC Adv. 2021, 11, 28000–28007. [CrossRef] [PubMed]
50. Dhavale, R.P.; Dhavale, R.P.; Sahoo, S.C.; Kollu, P.; Jadhav, S.U.; Patil, P.S.; Dongale, T.D.; Chougale, A.D.; Patil, P.B. Chitosan
coated magnetic nanoparticles as carriers of anticancer drug Telmisartan: pH-responsive controlled drug release and cytotoxicity
studies. J. Phys. Chem. Solids 2021, 148, 109749. [CrossRef]
51. Domagalski, J.T.; Xifre-Perez, E.; Tabrizi, M.A.; Ferre-Borrull, J.; Marsal, L.F. Magnetic nanoparticle decorated anodic alumina
nanotubes for fluorescent detection of cathepsin B. J. Colloid Interf. Sci. 2021, 584, 236–245. [CrossRef] [PubMed]
52. Doswald, S.; Stark, W.J. Preparation of Functionalized Carbon-Coated Cobalt Nanoparticles with Sulfonated Arene Derivatives, a
Study on Surface Functionalization and Stability. Chem.-Eur. J. 2021, 27, 4108–4114. [CrossRef] [PubMed]
53. Ehsanimehr, S.; Moghadam, P.N.; Dehaen, W.; Shafiei-Irannejad, V. PEI grafted Fe3 O4 @SiO2 @SBA-15 labeled FA as a pH-sensitive
mesoporous magnetic and biocompatible nanocarrier for targeted delivery of doxorubicin to MCF-7 cell line. Colloid Surface A
2021, 615, 126302. [CrossRef]
54. Fan, X.M.; Shen, J.J.; Xu, Y.Y.; Gao, J.; Zhang, Y.W. Metabolic integration of azide functionalized glycan on Escherichia coli cell
surface for specific covalent immobilization onto magnetic nanoparticles with click chemistry. Bioresour. Technol. 2021, 324, 124689.
[CrossRef]
55. Fernandez-Ponce, C.; Manuel, J.M.; Fernandez-Cisnal, R.; Felix, E.; Beato-Lopez, J.; Munoz-Miranda, J.P.; Beltran, A.M.; Santos,
A.J.; Morales, F.M.; Yeste, M.P.; et al. Superficial Characteristics and Functionalization Effectiveness of Non-Toxic Glutathione-
Capped Magnetic, Fluorescent, Metallic and Hybrid Nanoparticles for Biomedical Applications. Metals 2021, 11, 383. [CrossRef]
56. Habra, K.; McArdle, S.E.B.; Morris, R.H.; Cave, G.W.V. Synthesis and Functionalisation of Superparamagnetic Nano-Rods towards
the Treatment of Glioblastoma Brain Tumours. Nanomaterials 2021, 11, 2157. [CrossRef]
57. Jose, R.; Rinita, J.; Jothi, N.S.N. The synthesis and characterisation of curcumin loaded Ag ((1-X)) Ni (X) Fe-2 O-4 for drug delivery.
Mater. Technol. 2021, 36, 339–346. [CrossRef]
58. Kannan, K.; Mukherjee, J.; Mishra, P.; Gupta, M.N. Nickel Ferrite Nanoparticles as an Adsorbent for Immobilized Metal Affinity
Chromatography of Proteins. J. Chromatogr. Sci. 2021, 59, 262–268. [CrossRef]
59. Leitner, N.S.; Schroffenegger, M.; Reimhult, E. Polymer Brush-Grafted Nanoparticles Preferentially Interact with Opsonins and
Albumin. ACS Appl. Bio Mater. 2021, 4, 795–806. [CrossRef]
60. Martin, D.S.; Oropesa-Nunez, R.; de la Torre, T.Z.G. Evaluating the Performance of a Magnetic Nanoparticle-Based Detection
Method Using Circle-to-Circle Amplification. Biosensors 2021, 11, 173. [CrossRef]
61. Moskvin, M.; Huntosova, V.; Herynek, V.; Matous, P.; Michalcova, A.; Lobaz, V.; Zasonska, B.; Slouf, M.; Seliga, R.; Horak, D.
In vitro cellular activity of maghemite/cerium oxide magnetic nanoparticles with antioxidant properties. Colloid Surface B 2021,
204, 111824. [CrossRef] [PubMed]
Coatings 2023, 13, 1772 30 of 31

62. Nayeem, J.; Al-Bari, M.A.A.; Mahiuddin, M.; Rahman, M.A.; Mefford, O.T.; Ahmad, H.; Rahman, M.M. Silica coating of
iron oxide magnetic nanoparticles by reverse microemulsion method and their functionalization with cationic polymer P
(NIPAm-co-AMPTMA) for antibacterial vancomycin immobilization. Colloid Surface A 2021, 611, 125857. [CrossRef]
63. Reyes-Ortega, F.; Delgado, A.V.; Iglesias, G.R. Modulation of the Magnetic Hyperthermia Response Using Different Superparam-
agnetic Iron Oxide Nanoparticle Morphologies. Nanomaterials 2021, 11, 627. [CrossRef]
64. Rezaei, A.; Morsali, A.; Bozorgmehr, M.R.; Nasrabadi, M. Quantum chemical analysis of 5-aminolevulinic acid anticancer drug
delivery systems: Carbon nanotube, -COOH functionalized carbon nanotube and iron oxide nanoparticle. J. Mol. Liq. 2021,
340, 117182. [CrossRef]
65. Veloso, S.R.S.; Silva, J.F.G.; Hilliou, L.; Moura, C.; Coutinho, P.J.G.; Martins, J.A.; Testa-Anta, M.; Salgueirino, V.; Correa-
Duarte, M.A.; Ferreira, P.M.T.; et al. Impact of Citrate and Lipid-Functionalized Magnetic Nanoparticles in Dehydropeptide
Supramolecular Magnetogels: Properties, Design and Drug Release. Nanomaterials 2021, 11, 16. [CrossRef]
66. Wu, K.; Liu, J.M.; Saha, R.; Ma, B.; Su, D.Q.; Chugh, V.K.; Wang, J.P. Stable and Monodisperse Iron Nitride Nanoparticle
Suspension for Magnetic Diagnosis and Treatment: Development of Synthesis and Surface Functionalization Strategies. ACS
Appl. Nano Mater. 2021, 4, 4409–4418. [CrossRef]
67. Zare, M.; Sarkati, M.N. Chitosan-functionalized Fe3 O4 nanoparticles as an excellent biocompatible nanocarrier for silymarin
delivery. Polym. Adv. Technol. 2021, 32, 4094–4100. [CrossRef]
68. Zarinwall, A.; Asadian-Birjand, M.; Seleci, D.A.; Maurer, V.; Trautner, A.; Garnweitner, G.; Fuchs, H. Magnetic Nanoparticle-Based
Dianthin Targeting for Controlled Drug Release Using the Endosomal Escape Enhancer SO1861. Nanomaterials 2021, 11, 1057.
[CrossRef]
69. Zhalechin, M.; Dehaghi, S.M.; Najafi, M.; Moghimi, A. Magnetic polymeric core-shell as a carrier for gradual release in-vitro test
drug delivery. Heliyon 2021, 7, e06652. [CrossRef]
70. Zuk, M.; Gaweda, W.; Majkowska-Pilip, A.; Osial, M.; Wolski, M.; Bilewicz, A.; Krysinski, P. Hybrid Radiobioconjugated
Superparamagnetic Iron Oxide-Based Nanoparticles for Multimodal Cancer Therapy. Pharmaceutics 2021, 13, 1843. [CrossRef]
71. Ali, T.H.; Mandal, A.M.; Heidelberg, T.; Hussen, R.S.D. Sugar based cationic magnetic core-shell silica nanoparticles for nucleic
acid extraction. RSC Adv. 2022, 12, 13566–13579. [CrossRef]
72. Behr, J.; Carnell, L.R.; Stein, R.; Pfister, F.; Friedrich, B.; Huber, C.; Lyer, S.; Band, J.; Schreiber, E.; Alexiou, C.; et al. In Vitro Setup
for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions.
Cancers 2022, 14, 5978. [CrossRef]
73. Bin Jang, S.; Jin, S.M.; Kim, H.S.; Jeong, Y.Y.; Lee, S.J.; Hahn, S.; Lee, H.; Lee, H.S.; Kim, J.H.; Lee, D.Y. DAMP-modulating
nanoparticle for successful pancreatic islet and stem cell transplantation. Biomaterials 2022, 287, 121679. [CrossRef]
74. Gupta, R.; Gupta, P.; Footer, C.; Stenning, G.B.G.; Darr, J.A.; Pancholi, K. Tuneable magnetic nanocomposites for remote
self-healing. Sci. Rep. 2022, 12, 10180. [CrossRef]
75. Ikram, H.; Al Rashid, A.; Koc, M. Synthesis and characterization of hematite (alpha-Fe2 O3 ) reinforced polylactic acid (PLA)
nanocomposites for biomedical applications. Compos. Part C-Open 2022, 9, 100331. [CrossRef]
76. Liu, C.H.; Lin, C.H.; Chen, Y.J.; Wu, W.C.; Wang, C.C. Multifunctional magnetic nanocarriers for delivery of siRNA and shRNA
plasmid to mammalian cells: Characterization, adsorption and release behaviors. Colloid Surface B 2022, 219, 112861. [CrossRef]
77. Miola, M.; Verne, E. In situ reduction of Ag on magnetic nanoparticles with gallic acid: Effect of the synthesis parameters on
morphology. Nanomedicine 2022, 17, 499–511. [CrossRef]
78. Mun, H.; Chaban, Y.; Tabish, T.A.; Thorat, N.; Cowieson, N.; Owen, C.D.; Townley, H.E. CD44 and CD221 directed magnetic
cubosomes for the targeted delivery of helenalin to rhabdomyosarcoma cells. Nano Res. 2023, 16, 2915–2926. [CrossRef]
79. Mushtaq, S.; Shahzad, K.; Rizwan, M.; Ul-Hamid, A.; Abbasi, B.H.; Khalid, W.; Atif, M.; Ahmad, N.; Ali, Z.; Abbasi, R.
Magnetoelectric core-shell CoFe2 O4 @BaTiO3 nanorods: Their role in drug delivery and effect on multidrug resistance pump
activity in vitro. RSC Adv. 2022, 12, 24958–24979. [CrossRef]
80. Nayak, J.; Prajapati, K.S.; Kumar, S.; Vashistha, V.K.; Sahoo, S.K.; Kumar, R. Thiolated β-cyclodextrin modified iron oxide
nanoparticles for effective targeted cancer therapy. Mater. Today Commun. 2022, 33, 104644. [CrossRef]
81. Rocha, J.M.V.; de Souza, V.B.; Panunto, P.C.; Nicolosi, J.S.; da Silva, E.D.; Cadore, S.; Londono, O.M.; Muraca, D.; Tancredi, P.; de
Brot, M.; et al. In vitro and in vivo acute toxicity of a novel citrate-coated magnetite nanoparticle. PLoS ONE 2022, 17, e0277396.
[CrossRef]
82. Swain, S.K.; Phaomei, G.; Tripathy, S.K.; Yaiphaba, N.; Devi, R.B.; Nayak, S.; Parida, B.B. Effect of beta-cyclodextrin decoration on
structural, optical and magnetic properties of luminescent magnetic nanoparticles and its application as a drug carrier. J. Mol.
Struct. 2022, 1247, 131330. [CrossRef]
83. Szymczyk, A.; Drozd, M.; Kaminska, A.; Matczuk, M.; Trzaskowski, M.; Mazurkiewicz-Pawlicka, M.; Ziolkowski, R.; Malinowska,
E. Comparative Evaluation of Different Surface Coatings of Fe3 O4 -Based Magnetic Nano Sorbent for Applications in the Nucleic
Acids Extraction. Int. J. Mol. Sci. 2022, 23, 8860. [CrossRef]
84. Tang, X.Z.; Manamanchaiyaporn, L.; Zhou, Q.; Huang, C.Y.; Li, L.H.; Li, Z.Q.; Wang, L.C.; Wang, J.N.; Ren, L.; Xu, T.T.; et al.
Synergistic Integration and Pharmacomechanical Function of Enzyme-Magnetite Nanoparticle Swarms for Low-Dose Fast
Thrombolysis. Small 2022, 18, 2202848. [CrossRef]
Coatings 2023, 13, 1772 31 of 31

85. Toyos-Rodriguez, C.; Llamedo-Gonzalez, A.; Pando, D.; Garcia, S.; Garcia, J.A.; Garcia-Alonso, F.J.; De la Escosura-Muniz, A.
Novel magnetic beads with improved performance for Alzheimer’s disease biomarker detection. Microchem. J. 2022, 175, 107211.
[CrossRef]
86. Treder, N.; Roszkowaka, A.; Oledzka, I.; Baczek, T.; Plenis, A. Effects of Fe3 O4 Magnetic Nanoparticle Functionalization with
Ionic Liquids and a Double-Chained Surfactant on the Pretreatment of Plasma Samples during Drug Extraction. Anal. Chem.
2022, 94, 16587–16595. [CrossRef]
87. Urquizo, I.A.F.; Garcia, T.C.H.; Loredo, S.L.; Galindo, J.T.E.; Casillas, P.E.G.; Barron, J.C.S.; Gonzalez, C.C. Effect of Aminosilane
Nanoparticle Coating on Structural and Magnetic Properties and Cell Viability in Human Cancer Cell Lines. Part. Part. Syst.
Charact. 2022, 39, 2200106. [CrossRef]
88. Valdivia, V.; Gimeno-Ferrero, R.; Leal, M.P.; Paggiaro, C.; Fernandez-Romero, A.M.; Gonzalez-Rodriguez, M.L.; Fernandez, I.
Biologically Relevant Micellar Nanocarrier Systems for Drug Encapsulation and Functionalization of Metallic Nanoparticles.
Nanomaterials 2022, 12, 1753. [CrossRef]
89. Zohreh, N.; Karimi, N.; Hosseini, S.H.; Istrate, C.; Busuioc, C. Fabrication of a magnetic nanocarrier for doxorubicin delivery
based on hyperbranched polyglycerol and carboxymethyl cellulose: An investigation on the effect of borax cross-linker on
pH-sensitivity. Int. J. Biol. Macromol. 2022, 203, 80–92. [CrossRef]
90. Beltrame, J.M.; Ribeiro, B.B.P.; Guindani, C.; Candiotto, G.; Felipe, K.B.; Lucas, R.; Zottis, A.D.; Isoppo, E.; Sayer, C.; de Araujo,
P.H.H. Coating of SPIONs with a Cysteine-Decorated Copolyester: A Possible Novel Nanoplatform for Enzymatic Release.
Pharmaceutics 2023, 15, 1000. [CrossRef]
91. Chauhan, M.; Basu, S.M.; Qasim, M.; Giri, J. Polypropylene sulphide coating on magnetic nanoparticles as a novel platform for
excellent biocompatible, stimuli-responsive smart magnetic nanocarriers for cancer therapeutics. Nanoscale 2023, 15, 7384–7402.
[CrossRef] [PubMed]
92. Jalali, S.; Moghadam, P.N.; Shafiei-Irannejad, V. Synthesis of Magnetic Nanocarrier Conjugated by Folate Based on Tragacanth
and In Vitro Investigation of their Efficiency on Breast Cancer Cells. Starch-Starke 2023, 75, 2200092. [CrossRef]
93. Liu, L.; Yang, Z.J.; Liu, C.B.; Wang, M.Y.; Chen, X. Preparation of PEI-modified nanoparticles by dopamine self-polymerization for
efficient DNA delivery. Biotechnol. Appl. Biochem. 2023, 70, 824–834. [CrossRef] [PubMed]
94. Nguyen, T.N.; Tran, Q.H.; Terki, F.; Charnay, C.; Dumail, X.; Reibel, C.; Cazals, G.; Valette, G.; Jay-Allemand, C.; Bidel, L.P.R.
Aggregation of magnetic nanoparticles functionalized with trans-resveratrol in aqueous solution. Discov. Nano 2023, 18, 64.
[CrossRef] [PubMed]
95. Kovrigina, E.; Poletaeva, Y.; Zheng, Y.; Chubarov, A.; Dmitrienko, E. Nylon-6-Coated Doxorubicin-Loaded Magnetic Nanoparticles
and Nanocapsules for Cancer Treatment. Magnetochemistry 2023, 9, 106. [CrossRef]
96. Baldea, I.; Petran, A.; Florea, A.; Sevastre-Berghian, A.; Nenu, I.; Filip, G.A.; Cenariu, M.; Radu, M.T.; Iacovita, C. Magnetic
Nanoclusters Stabilized with Poly[3,4-Dihydroxybenzhydrazide] as Efficient Therapeutic Agents for Cancer Cells Destruction.
Nanomaterials 2023, 13, 933. [CrossRef]
97. Urquizo, I.A.F.; Tozcano, D.I.M.; Gómez, L.E.V.; Pérez, J.A.R.; González, C.C. Enhancing the Cytocompatibility of Cobalt-
Iron Ferrite Nanoparticles Through Chemical Substitution and Surface Modification. Adv. Mater. Interfaces 2023, 10, 2300206.
[CrossRef]
98. Toderascu, L.I.; Sima, L.E.; Orobeti, S.; Florian, P.E.; Icriverzi, M.; Maraloiu, V.-A.; Comanescu, C.; Iacob, N.; Kuncser, V.;
Antohe, I.; et al. Synthesis and Anti-Melanoma Activity of L-Cysteine-Coated Iron Oxide Nanoparticles Loaded with Doxorubicin.
Nanomaterials 2023, 13, 621. [CrossRef]
99. Xu, X.; Xiang, H.J.; Wang, Z.J.; Wu, C.J.; Lu, C.C. Doping engineering and functionalization of iron oxide nanoclusters for
biomedical applications. J. Alloys Compd. 2022, 923, 166459. [CrossRef]
100. Upadhyay, K.; Tamrakar, R.K.; Thomas, S.; Kumar, M. Surface functionalized nanoparticle A boon to biomedical science.
Chem.-Biol. Interact. 2023, 380, 110537. [CrossRef]
101. Popova, V.; Dmitrienko, E.; Chubarov, A. Magnetic Nanocomposites and Imprinted Polymers for Biomedical Applications of
Nucleic Acids. Magnetochemistry 2023, 9, 12. [CrossRef]
102. Mulens-Arias, V.; Rojas, J.M.; Barber, D.F. The Use of Iron Oxide Nanoparticles to Reprogram Macrophage Responses and the
Immunological Tumor Microenvironment. Front. Immunol. 2021, 12, 693709. [CrossRef] [PubMed]
103. Bilal, M.; Iqbal, H.M.N.; Adil, S.F.; Shaik, M.R.; Abdelgawad, A.; Hatshan, M.R.; Khan, M. Surface-coated magnetic nanostructured
materials for robust bio-catalysis and biomedical applications-A review. J. Adv. Res. 2022, 38, 157–177. [CrossRef] [PubMed]
104. Bohara, R.A.; Thorat, N.D.; Pawar, S.H. Role of functionalization: Strategies to explore potential nano-bio applications of magnetic
nanoparticles. RSC Adv. 2016, 6, 43989–44012. [CrossRef]
105. Mittal, N.; Kundu, A.; Pathania, A.R. A review of the chemical synthesis of magnetic nano-particles and biomedical applications.
Mater. Today Proc. 2023. [CrossRef]

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