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Manganese-based nanomaterials in diagnostics and

Cite this: RSC Adv., 2024, 14, 14722
chemodynamic therapy of cancers: new
development
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

Meiyan Wu, †a Yuan Liao, †a Di Guo,a Mingyue Zhai,a Desong Xia,a

Zhikun Zhang,*b Xiyu Liu*a and Yong Huang*a

In the realm of cancer treatment, traditional modalities like radiotherapy and chemotherapy have achieved
certain advancements but continue to grapple with challenges including harm to healthy tissues, resistance
to treatment, and adverse drug reactions. The swift progress in nanotechnology recently has opened
avenues for investigating innovative approaches to cancer therapy. Especially, chemodynamic therapy
(CDT) utilizing metal nanomaterials stands out as an effective cancer treatment choice owing to its
minimal side effects and independence from external energy sources. Transition metals like manganese
are capable of exerting anti-tumor effects through a Fenton-like mechanism, with their distinctive
magnetic properties playing a crucial role as contrast agents in tumor diagnosis and treatment. Against
this backdrop, this review emphasizes the recent five-year advancements in the application of
manganese (Mn) metal ions within nanomaterials, particularly highlighting their unique capabilities in
catalyzing CDT and enhancing MRI imaging. Initially, we delineate the biomedical properties of
Received 3rd March 2024
Accepted 17th April 2024
manganese, followed by an integrated discussion on the utilization of manganese-based nanomaterials
in CDT alongside multimodal therapies, and delve into the application and future outlook of manganese-
DOI: 10.1039/d4ra01655f
based nanomaterial-mediated MRI imaging techniques in cancer therapy. By this means, the objective is
rsc.li/rsc-advances to furnish novel viewpoints and possibilities for the research and development in future cancer therapies.

effects and the absence of a need for external energy sources, it

1 Introduction has emerged as an effective method for treating cancer.7 CDT is
As indicated by recent cancer statistics,1 cancer remains driven by the Fenton reaction and Fenton-like reaction,8 which
a signicant challenge to human well-being, with the are considered potential strategies for tumor cell treatment.9
advancement of effective therapies being a primary aim of The Fenton reaction involves Fe2+/Fe3+ redox, catalyzing intra-
cancer nanomedicine.2 Presently, radiotherapy and chemo- cellular hydrogen peroxide (H2O2) to produce highly toxic ROS.
therapy still form the foundation of clinical cancer treatments.3 Fenton-like processes encompass reactions in which Fe3+, iron-
While signicant achievements have been made with these two bearing minerals, and various transition metals, including Cu,
treatments, ionizing radiation can irreversibly harm adjacent Ag, Mn, and Ni, can expedite or act as surrogates for Fe2+ in the
normal tissues, thus restricting the radiation dose delivered to catalysis of H2O2.10 For radiotherapy and chemotherapy, high
the patient.4 Additionally, resistance and toxicity associated doses of drugs can cause severe damage to normal tissues, and
with chemotherapy can lead to various side effects in patients,5 even peripheral neuropathy in cases of overexpression and
indicating certain limitations in these therapies. The burgeon- permanent sequelae and disability in a large percentage of
ing growth of biotechnology and nanotechnology in recent years cancer survivors.11,12 In addition, compared with photodynamic
has revitalized new therapeutic approaches. In 2016, Tang and therapy (PDT), CDT does not produce complications such as
his team initially coined the term CDT.6 Due to its reduced side pain, burns, and oedema.12 At the same time, CDT does not
require exogenous stimulation and there is no damage to
normal tissues caused by the high-frequency ultrasound in
a
State Key Laboratory of Targeting Oncology, National Center for International sonodynamic therapy (SDT). Therefore, CDT is currently widely
Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting regarded as a new treatment method with fewer side effects.13
Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Owing to the presence of various electrolyte ions (like
Therapy, Guangxi Medical University, Nanning 530021, China. E-mail:
calcium and phosphates) and bioactive groups in tissues and
[email protected]; [email protected]
b
cells, they could inuence CDT through chelation with iron ions
The Second Affiliated Hospital of Guangxi Medical University, China. E-mail:
[email protected] or reaction with cytotoxic hydroxyl radicals (cOH).14 Many
† These authors contributed equally to this work. research ndings show that the efficacy of CDT in treating

14722 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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cancer is frequently constrained by the proportion of metal United States Food and Drug Administration (FDA) suggests the
ions, requiring the addition of low-valent metal ions in the daily intake of manganese for adult males is 2.3 mg per day and
synthesis of nanomaterials to boost CDT's effectiveness.15 for females 1.8 mg per day.19 Leveraging its catalytic and redox
Nanomaterials with Mn2+ may boost CDT by triggering oxidative capabilities, manganese modulates a spectrum of enzymes,
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stress responses in cells due to the released Mn2+, and also act including manganese superoxide dismutase (SOD), glutamine
as MRI contrast agents for tumor imaging during the thera- synthetase, and pyruvate carboxylase, among others. This
peutic process.16 Modern medical imaging modalities, modulation plays a crucial role in maintaining the metabolic
including X-ray computed tomography (CT), positron emission balance and redox equilibrium vital to life's processes.
tomography (PET), and magnetic resonance imaging (MRI), Furthermore, manganese superoxide dismutase (MnSOD)
play a pivotal role in therapeutic interventions. MRI stands out serves as the principal antioxidant within mitochondria,
from CT and PET scans as it does not expose the body to radi- capable of catalyzing the decomposition of superoxide radicals
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

ation, and is extensively used in clinics for medical diagnosis, into hydrogen peroxide to achieve a tumor-killing effect.20 Via
disease staging, and follow-ups. Laboratory research benets these metalloenzymes, manganese is instrumental in
from the visualization of tumor sites, contributing to the early numerous biological processes including development, diges-
detection of tumors. Integrating therapy with diagnosis to tion, reproduction, antioxidative protection, energy generation,
enable concurrent therapy monitoring and diagnosis is an immune response, and the control of neuronal activity.21
anticipated and ideal direction in the recent advancements of Manganese has been shown to enhance the immune responses
functional imaging technology. in vertebrates, including humans, rodents, birds, and sh.22
Therefore, this review rst introduces the biomedical prop- Conversely, excess manganese tends to accumulate in the liver,
erties of manganese, and starting from its CDT and MRI char- pancreas, bones, kidneys, and brain, with the brain being the
acteristics, it focuses on the diverse applications of manganese main target for manganese toxicity, causing neurotoxicity and
(Mn)-based nanomaterials in CDT, and delves into the appli- other detrimental impacts.21 The imbalance of manganese in
cation prospects of its longitudinal relaxation time (T1)- neurological conditions highlights its critical role in brain
enhanced MRI characteristics combined with various imaging development and essential neurophysiological functions.
methods in precise tumor monitoring and treatment, aiming to Genetic disorders affecting manganese transport, resulting in
suggest ways to enhance the application depth and breadth of neurodevelopmental and neurodegenerative syndromes,
manganese-based nanomaterials in the future. underscore its neurotoxic capacity. Additionally, disruptions in
manganese balance are associated with Parkinson's disease and
other neurodegenerative diseases, including Alzheimer's
2 Manganese's biological disease and Huntington's disease.23 Within the human brain,
characteristics typical Mn concentrations range from 20.0 mM to 52.8 mM, and
when Mn concentrations are between 60.1 and 158.4 mM, brain
Manganese, found in minuscule quantities in the cells of living
function becomes abnormal.24 The normal range for free
organisms, is a vital trace element necessary for the life
manganese concentration in the blood is between 0.029 and 1.2
processes of both animals and plants. It performs numerous
mM, and it is within this range that the application of Mn-based
physiological roles, encompassing not just the promotion of
nanomaterials is deemed safe.25
bone growth and development, and the maintenance of normal
glucose and fat metabolism, but also exerting a signicant
inuence on oxidative stress and hematopoiesis. Signicantly, 2.2 Chemodynamic therapy and tumor microenvironment
Mn exhibits distinct functionalities in nanomedicine, such as regulation
immune defense, CDT, MRI, and TME reconstruction, offering
Chemodynamic therapy (CDT) represents a novel therapeutic
ample prospects for the development of versatile nanomedicine
approach, which involves in situ treatment at the tumor site by
platforms. The specic attributes of Mn are outlined below
generating cOH through Fenton or Fenton-like reactions.
(Fig. 1), anticipated to inform the design of Mn-based multi-
Manganese, among other metal nanomaterials, has Fenton or
functional nano-platforms.
Fenton-like properties that dissolve into metal ions under the
mildly acidic conditions of the TME, initiating the Fenton
2.1 Physiological functions reaction to produce excess H2O2, generating cOH, thereby trig-
Manganese, both a necessary nutrient and a crucial heavy gering cell apoptosis and inhibiting tumors.6,26 The tumor
metal, is found naturally in the environment. The daily required microenvironment (TME) is distinguished by mild acidity,
energy for functions such as antioxidation, energy metabolism, elevated H2O2 concentrations, reduced catalase activity, and
immune function, and others are obtained through dietary hypoxia, providing an optimal environment and nutrients that
sources.17 It forms part of several physiologically important facilitate tumor growth and metastasis, making it an ideal
enzymes and is a necessary cofactor for various enzyme systems, target for tumor therapy.6,27 Tumor cells are chiey character-
including manganese-specic glycosyltransferases and phos- ized by elevated Reactive Oxygen Species (ROS) levels and
phoenolpyruvate carboxylase. Such enzymes are instrumental changes in redox state. ROS denotes substances with high
in regulating metabolic activities including cholesterol oxidative potential featuring oxygen radicals, encompassing
synthesis, gluconeogenesis, and cartilage development.18 The peroxides, superoxides, singlet oxygen, and hydroxyl radicals

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Fig. 1 Manganese has the following four main functions: (1) physiological functions; (2) chemodynamic therapy and tumor microenvironment
regulation; (3) immune defense; (4) magnetic resonance imaging.

among others.26,28,29 Within organisms, ROS serve as crucial consuming the overexpressed antioxidant GSH in cells, signif-
cellular signaling molecules, playing a key role in the regulation icantly reducing its content, and increasing the sensitivity of
of diverse physiological processes and the maintenance of the tumor cells to ROS. Furthermore, within the acidic conditions
cells' normal redox equilibrium. The generation of endogenous of the tumor microenvironment (TME), MnO2 nanoparticles
ROS primarily originates from the aerobic metabolism in interact with the excessively present H2O2 in the tumor, gener-
cellular mitochondria. Under normal physiological conditions, ating a signicant quantity of oxygen.33 In addition to Mn-based
the concentration of ROS can be regulated to remain within nanomaterials, other nanomaterials capable of inducing CDT
a stable range, playing a signicant role in regulating cell include other metal nanomaterials (such as iron-based, copper-
signaling, bacterial clearance, mediating inammation, and based, etc.), silicon-based nanomaterials, and carbon-based
adjusting protein functions among other metabolic pathways.30 nanomaterials, all of which have certain defects in their appli-
When ROS levels surpass the tolerance threshold, it can result cation. The Fenton reaction is primarily catalyzed by low-
in oxidative stress, leading to irreversible, nonspecic damage valence metal ions, but the low reaction rate of the reduction
to proteins, lipids, and DNA. The delivery characteristics of of Fe3+ to Fe2+ greatly limits the Fenton reaction.34 Moreover, Cu
Mn2+ and the consumption behavior of glutathione help to exhibits greater toxicity than Fe or Mn in usage.35 Silicon-based
tackle the issue of diminished CDT effectiveness due to the nanomaterials are oen used as auxiliary nanomaterials,
reduction of intracellular glutathione (GSH).31 The increase in making it difficult to promote the Fenton reaction process and
cytotoxic hydroxyl radicals (cOH) can induce DNA and protein resulting in extremely slow degradation speeds. Furthermore,
damage, accelerating the apoptosis of cancer cells. It has also the high-temperature carbonization process used in the prep-
been found that MnO2 nanostructures decompose H2O2 in the aration of carbon-based nanomaterials does not allow for the
TME, achieving an effect of alleviating tumor hypoxia.32 The uniform dispersion of the target carriers, leading to the risk of
process involves MnO2 nanoparticles undergoing redox reac- highly aggregated nanomaterials in blood transport.36 In
tions, producing Mn2+ and glutathione disulde (GSSG), contrast, Mn-based nanomaterials offer relatively safe and

14724 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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efficient treatment, and advantageous for ROS/oxygen- making them unsuitable for prolonged tissue scanning. The
dependent tumor therapy by modulating TME, which have signal voids appearing in iron oxide-based contrast agents are
great potential in tumor chemodynamic therapy. indistinguishable from those produced by the metallic mate-
rials themselves, thus limiting their clinical application.46 Mn-
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2.3 Immune defense function based contrast agents are effective MRI relaxants and are
among the most common pH-responsive magnetic resonance
Mn plays an immunomodulatory role in the body.37 Beyond
nano-contrast agents. They are sensitive to the weakly acidic
altering the tumor microenvironment (TME), this approach also
and reductive conditions of the TME. In an acidic environment,
amplies tumor treatment efficacy through the activation of
Mn(II) ions with ve unpaired electrons can be released,
Mn2+-associated immune pathways, effectively responding to
increasing the likelihood of Mn(II) paramagnetic centers con-
the TME conditions, thereby alleviating hypoxia, GSH deple-
tacting water molecules, thus signicantly shortening the
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

tion, and other immunosuppressive conditions. The stimulator

longitudinal relaxation time of water protons, yielding robust
of interferon genes (STING) promotes signal transduction and
high signals without adverse effects. Mn(II) can selectively enter
the production of type I IFN through the activation of the TBK1-
neurons via voltage-gated calcium channels, inducing neuronal
IRF3 axis, and can directly participate in the detection of
activity.47 Within safe dosage limits, longitudinal imaging of the
intracellular bacteria.38 Cyclic GMP-AMP synthase (cGAS)
whole brain dynamics of the same subject can be repeated over
produces the endogenous second messenger 20 30 -cyclic GMP-
several weeks.48 Manganese contrast agents have similar posi-
AMP (20 30 -cGAMP), which directly binds to STING, promoting
tive contrast enhancement capabilities; binding with proteins
its activation.39 The early immune system's targeting and killing
can increase the relaxivity of Mn2+ and enhance contrast.49 In
of tumor cells depend on dendritic cells (DCs) producing type I
relation to boosting the contrast in T1 imaging for heightened
interferons (IFNs) and recruiting CD8+ T cells, while the STING
sensitivity in cancer diagnosis, Yang et al., focusing on nano-
pathway plays a unique role in this critical step of anti-tumor
manganese oxide, discovered that the surface area, volume,
immunity by attracting CD8+ T cells to the TME.40 Moreover,
and the r2/r1 ratio of manganese ions have both positive and
the cGAS-STING pathway can initiate the synthesis of antiviral
negative impacts on the sensitivity of T1 imaging. MnO octa-
cytokines belonging to the type I interferon family, leading to
hedra, featuring a high longitudinal relaxation rate (r1) value of
the induction of hundreds of interferon-stimulated genes (ISGs)
20.07 mM−1 s−1, showed signicant improvement in liver T1
that possess diverse antiviral activities.41 Mn2+ act as potent
imaging. Furthermore, both liver and subcutaneous tumors
activators of cGAS, triggering cells to produce type I IFNs and
remained detectable even at ultra-low dosages.50 Based on these
cytokines even without any infection. This activation markedly
characteristics, manganese-based nanomaterials are CAs with
fosters the maturation and antigen presentation of DCs and
broad application prospects in T1-weighted MRI.
macrophages in a cGAS-STING-dependent way, enhancing the
In summary, leveraging the ROS generation capabilities and
activation of CD8+ T cells and NK cells.25 Additionally, Mn2+
other properties inherent to Mn2+ Fenton-like reactions, Mn2+
boosts the detection of viral infections in cells by heightening
can be utilized across a spectrum of cancer treatment modali-
the sensitivity of the DNA sensor cGAS and its downstream
ties, including CDT and immunotherapy. Its ability to modulate
adaptor protein STING. It also promotes the activity of the
the TME amplies the efficacy of cancer therapies. Additionally,
STING pathway by strengthening the binding affinity of cGAMP-
its utility in MRI provides a means to track the progress of
STING.42 Based on these ndings, Mn2+ demonstrates great
tumor treatment, ascertain the in vivo biological distribution,
potential in tumor immunology, with its product IFN-I having
and assess the effectiveness of cancer therapies. Therefore, Mn-
immunomodulatory functions, initiating anti-tumor responses
based nanomaterials offer the exibility to be precisely engi-
through CD8+ T and NK cells.
neered and developed into traceable, multifunctional nano-
platforms for efficacious tumor therapy. Here, we provide
2.4 Magnetic resonance imaging a brief introduction to the research progress on the application
Magnetic Resonance Imaging (MRI), a medical imaging of manganese-based multifunctional nano-platforms in CDT
modality devoid of X-rays and ionizing radiation, has emerged therapy, including multimodal synergistic treatments related to
as a crucial non-invasive technique for molecular imaging. This CDT and imaging-guided tumor therapy. Finally, we explore the
prominence is attributed to its unparalleled signal-to-noise obstacles and prospective advancements in the application of
ratio, superior spatial resolution, and exceptional contrast in Mn-based CDT for cancer treatment.
so tissues. Compared to CT scans, MRI is still considered
a better choice. Commonly, paramagnetic metals as well as
superparamagnetic and ferromagnetic substances are used as 3 Chemodynamic therapy involving
CAs due to their ability to magnetize in an external magnetic multimodal synergistic treatment
eld.43 Currently, the most frequently utilized T1 paramagnetic
metal contrast agents comprise Mn-based, gadolinium-based, Normally, natural CDT agents (such as Fe ions) are present in
and iron oxide-based agents,44 while gadolinium-based the body, but the low concentration of Fe ions in cancer cells
contrast agents are clinically useful, they are associated with results in reduced Fenton reaction efficiency, rendering the
signicant nephrotoxicity.45 Furthermore, their short circula- amount of catalytically generated cOH insufficient to trigger
tion time prevents the acquisition of high-resolution images, apoptosis in cancer cells. Conversely, Mn-based nanomaterials

© 2024 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2024, 14, 14722–14741 | 14725
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can supply ample CDT agents, facilitating CDT therapy, and for treating cancer. It primarily utilizes potent cytotoxic drugs
when used in conjunction with other therapies, they can further that target rapidly dividing cells through various mechanisms
enhance the efficacy of tumor treatment. Meanwhile, Mn-based to suppress tumor growth and prevent distant metastasis.57
nanomaterials, as nanomedicines, satisfy the properties of However, the use of these chemotherapy drugs is limited by
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stability, biodegradability, biocompatibility and targeting, and resistance, selectivity, and inevitable side effects. They are only
the advantage of targeting is also a major feature for CDT employed when their therapeutic benets surpass their chem-
treatment. The following briey introduces some Mn-based ical toxicity, signicantly constraining their effectiveness in
nanomaterials targeting CDT and summarises the pros and treating malignancies and thus limiting their efficacy in cancer
cons of certain therapies (including chemotherapy, radio- therapy.57,58 Hence, pursuing treatments that target specic
therapy, starvation therapy, gas therapy, PDT, PTT, and others), tumor sites in conjunction with other materials is a crucial
as well as studies on their combined treatment with CDT. developmental direction. Encapsulation or incorporation of
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

drugs into nanocarriers can signicantly enhance their solu-

3.1 Mn-based nanomaterials targeting CDT bility, stability, and bioavailability, thereby enabling targeted
distribution within the body. Such modications in the drugs'
The commonly used cancer treatment modalities, such as
inherent physicochemical properties and delivery efficiency
surgery, radiation therapy, and chemotherapy, suffer from limi-
culminate in improved therapeutic outcomes for the encapsu-
tations like poor targeting, reduced effectiveness, and prolonged
lated or loaded drugs.59 Tumor tissues exhibit heterogeneity,60
duration of action.51 The signicant rationale behind selecting
with a substantial presence of cells resistant to chemotherapy.
nanomedicine for cancer therapy lies in the targeted approach of
Once most of the sensitive cells are eliminated, the remaining
nanomedicines. Targeted nanoparticles are capable of directing
ones may develop resistance, potentially causing tumor resis-
drug delivery to the TME, managing the release schedule of the
tance or recurrence. Zhong et al. developed TPP-DOX@MnBSA
medication, minimizing the off-target adverse reactions and
(TD@MB) nanoparticles, using bovine serum albumin (BSA)
potential toxicity, which, in turn, improves the outcomes of
as a carrier, loaded with triphenylphosphine-modied doxoru-
cancer therapy.52 A common method to improve the targeting of
bicin (TPP-DOX) and manganese, to combine chemotherapy
nanomaterials is to modify the surface of nanoparticles with
with CDT. The uniform and stable spherical nanoparticles
different small molecules to increase specic binding affinity,
enhance drug absorption and ensure mitochondrial targeted
thereby achieving targeting of specic sites or cells.53 Chen et al.
delivery, increasing intracellular ROS and highly toxic cOH,
designed nanohybrids (TSMs), which use transferrin (Tf) as
thereby effectively inhibiting the proliferation of both chemo-
a modied small molecule to target the overexpression of the
sensitive and chemoresistant MCF-7 breast cancer cells.
transferrin receptor (TfR) on the surface of cancer cells, and can
Furthermore, TD@MB is capable of downregulating proteins
deliver the nanomedicine targeted delivery to subcutaneous
associated with stem cells and metastasis, thereby decreasing
tumor sites. Meanwhile, the other two components included in
the stemness and metastatic potential of tumors. In vivo
TSM, MnO2 and semiconductor polymers (SP), also play different
experiments using a tumor-bearing zebrash model demon-
anti-tumor roles; manganese dioxide can be used as a catalyst for
strated that TD@MB exhibits excellent anti-tumor effects, along
CDT, and semiconductor polymers can be used as a nano-
with good tumor targeting and biocompatibility. In vivo exper-
photosensitizer for PDT, mediating the combined treatment of
iments using the 4T1 tumor-bearing nude mouse model and the
PDT and CDT and generating abundant ROS, thus enhancing the
MCF-7 tumor-bearing zebrash model were conducted to verify
targeted anti-tumor effect.54 Besides Tf, there are many
the biodistribution, excellent tumor targeting, and biocompat-
commonly used small molecule ligands, including arginine-
ibility of [email protected]
glycine-aspartate (RGD) peptide, triphenylphosphine (TPP), etc.
For example, Li et al. modied RGD peptide on indocyanine
green (ICG) labeled Mn-based nanomaterials carrying lncRNA 3.3 Mn-based CDT and radiotherapy
OUM1 and its target gene siPTPRZ1 and cisplatin. Due to the
Radiotherapy (RT) is a signicant approach extensively utilized
specic binding of RGD peptide with the overexpressed integrin
for cancer treatment in clinical settings. Its underlying mech-
avb3 receptor on the tumor cell membrane, specic targeting of
anism entails the generation of ROS and other free radicals,
tumor cells can be achieved.55 Zhong et al. designed a nano-
leading to molecular structural damage, including DNA single
preparation, TPP-DOX@MnBSA (TD@MB), which modies DOX
and double-strand breaks. This process directly harms DNA,
with TPP as a ligand, with mitochondria as the entry therapeutic
curtails cell proliferation, and may induce cell death or
target. TPP as a mitochondrial ligand can be absorbed by the
apoptosis.61,62 However, the efficacy of radiotherapy is inu-
mitochondrial membrane, and targeting TPP-DOX to the mito-
enced by various factors. Initially, the tumor microenviron-
chondria can achieve tumor cell killing by destroying the mito-
ment's weak acidity, hypoxia, and high glutathione levels affect
chondria, while synergizing with Mn2+-mediated CDT can
radiotherapy's outcomes.63 Secondly, although hypoxic cells
amplify the tumor-killing effect.56
release more ROS than normal cells, studies indicate that under
hypoxic conditions, the antioxidant defense network in hypoxic
3.2 Mn-based CDT and chemotherapy cells is more actively engaged, quickly diminishing ROS damage
Chemotherapy stands as a prevalent anti-cancer drug modality to tumor cells.64 Additionally, the hypoxic conditions within
for systemic therapy and ranks among the most potent methods tumors can stimulate the expression of hypoxia-inducible factor

14726 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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HIF-1, which in turn promotes tumor cell proliferation and bolstering anti-tumor efficacy.69 For example, Xiao and
survival. This adaptation indirectly diminishes the effectiveness colleagues constructed a multifunctional nanotherapeutic
of radiotherapy.65 Therefore, tissue hypoxia stands as one of the platform comprising manganese carbonate-deposited iron
primary causes behind the failure of radiotherapy treatments. oxide nanoparticles (MCDION-Se) coated with nano-selenium
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Combining radiation with pharmacological ROS inducers has (nano-Se). MCDION-Se releases a signicant amount of Mn2+,
become a focus of research. This section provides a brief catalyzing the conversion of H2O2 into hydroxyl radicals (cOH)
summary of the combined treatment of radiation and CDT. through Fenton-like reactions, effectively triggering cancer cell
CDT can increase the levels of ROS in the TME by catalyzing the apoptosis. Moreover, the nano-Se on MCDION-Se substantially
formation of cOH from H2O2, thereby killing tumor cells,26 activates superoxide dismutase (SOD) within tumor tissues,
indicating that both can play a synergistic role in combating facilitating the production of superoxide anion radicals
cancer. Various nanosystems have been developed that can be (SOARs). Subsequently, SOD catalyzes SOARs to generate high
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used not only for CDT but also for radiotherapy. Chen and levels of H2O2, further enhancing the efficiency of CDT.
colleagues synthesized a magnetic core–shell nanoplatform, Simultaneously, nano-Se and Mn2+ inhibit the production of
Fe3O4@MnO2. Manganese dioxide (MnO2) as the shell layer adenosine triphosphate (ATP), leading to starvation of cancer
reacts with intracellular glutathione to generate Mn2+. In the cells. Upon subcutaneous implantation of HeLa cells in BALB/c
presence of isoniazid (INH), Mn2+ decomposes hydrogen mice and subsequent intravenous administration, observations
peroxide (H2O2) into hydroxyl radicals (cOH). Additionally, revealed that MCDION-Se treatment was effective and did not
Fe3O4 can react with endogenous H2O2 to further damage tumor lead to resistance.70
cells. Simultaneously, MnO2 has the capability to catalyze the
conversion of H2O2 into O2, alleviating tumor hypoxia and 3.5 Mn-based CDT and gas therapy
enhancing radiotherapy efficacy. The CDT mediated by INH and
Gas therapy (GT), with its high efficacy, biocompatibility, and
Fe3O4@MnO2 enhanced the therapeutic effect of radiotherapy
biosafety, has attracted widespread attention in nanomedicine.
in vitro, and in vivo experiments in Aicardi-Goutières syndrome
Gases employed in cancer treatment mainly encompass
tumor-bearing mice conrmed its good radiosensitizing
hydrogen, carbon monoxide (CO), hydrogen sulde (H2S), and
effect.66 Lin and colleagues created a nanocapsule containing
nitric oxide (NO).71,72 However, therapeutic gases are typically
near-infrared (NIR) uorescent dye (IR1061) within gold-
unstable and face challenges in precise accumulation and
manganese oxide nanoparticles (JNP), which are also size-
controlled release at tumor sites, leading to difficulties in direct
changeable, glutathione-responsive radiosenitizing nano-
administration or delivery clinically. Utilizing metal–organic
vesicles (JNP Ve). When exposed to glutathione (GSH), JNP Ve
frameworks (MOFs), known for their structural diversity and
decomposes into gold nanoparticles (Au NPs) and manganese
high surface areas, can effectively transport and release gases.
ions. Au NPs can generate ROS under X-ray irradiation and
Moreover, combining gas therapy with other treatments can
penetrate deeper into the tumor. Meanwhile, Mn2+ can induce
synergistically enhance the efficacy of these therapies.71–73 He
CDT via a Fenton-like reaction, enhancing the efficacy of RT. In
et al. synthesized a biodegradable nanotherapeutic drug
vivo experiments initially established a subcutaneous MCF-7
(MnS@BSA) that combines gas therapy and CDT. This nano-
tumor-bearing mouse model for image-guided therapy,
particle is pH-responsive, releasing H2S and Mn2+ under acidic
showing astonishing combined treatment effects, followed by
conditions. The released H2S is used for gas therapy, Mn2+
the development of an in situ hepatocellular carcinoma mouse
undergo a Fenton-like reaction to generate highly toxic cOH for
model that demonstrated JNP Ve's effective anti-tumor activity
CDT, and a subcutaneous 4T1-Luciferase BALB/c mouse model
against deep-seated tumors.67
is used to evaluate the anti-tumor effect and drug distribution of
MnS@BSA through MRI and uorescence imaging.74 Zhao and
3.4 Mn-based CDT and starvation therapy team encapsulated manganese dioxide nanoparticles and
carbonyl iron (FeCO) in mesoporous silica nanoparticles,
The sustained provision of nutrients and oxygen is crucial for
creating a nanomedicine, FeCO–MnO2@MSN, for combined
the survival and proliferation of tumors. Interruption of oxygen
CDT and gas therapy. Under the acidic pH of the TME, the
supply can lead to hypoxia, cell damage, apoptosis, and
disintegration releases ROS from MnO2, and the produced cOH
necrosis. Angiogenesis induction is essential for tumor growth,
further triggers the breakdown of FeCO into CO, causing
and anti-angiogenesis treatment, a crucial part of starvation
damage to the DNA and mitochondria of cancer cells, thereby
therapy (ST), is among the most effective clinical approaches to
producing a synergistic anticancer effect both in vitro and in
hinder tumor growth.68 Employing CDT as a standalone treat-
vivo. Additionally, the authors employed a 4T1 tumor-bearing
ment faces challenges, including the low catalytic efficiency of
mouse model for intravenous drug delivery, aligning with in
metal ions and the inadequate levels of endogenous H2O2.
vitro ndings, which demonstrates the synergistic action
Similarly, using ST alone offers limited resistance to tumors.
between CDT and gas therapy.75
The “metal-oxidase” cascade catalytic system, which introduces
cell metabolic oxidases into metal-based nanoplatforms, effec-
tively resolves the limitations of both therapies individually. It 3.6 Mn-based CDT and photodynamic therapy
supplies ample H2O2 and an appropriate acidic environment for Photodynamic therapy (PDT) is a minimally invasive treatment
CDT, further enhancing the synergistic impact with ST and thus approach that revolves around the interaction between

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a photosensitizer, light of a specic wavelength, and molecular a GSH-activated Fenton reaction, demonstrate outstanding
oxygen, selectively destroying tissues. Aer being injected into combined CDT and PDT effects. Data from studies in in vitro
the body, the photosensitizer selectively accumulates in tumor and in vivo MCF-7 tumor-bearing nude mouse experiments
tissues. Under exposure to light of a specic wavelength, the show that under external laser irradiation, mCMSNs are capable
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

generated energy converts molecular oxygen into reactive of catalyzing the breakdown of endogenous H2O2 into O2, ulti-
oxygen, leading to the death of tumor cells.76 PDT has the mately generating toxic 1O2, thereby alleviating the tumor
advantages of minimal side effects and low resistance. However, hypoxic microenvironment. GSH induces the biodegradation of
oxygen is a crucial raw material for inducing PDT, and the mCMSNs, releasing Cu+ and Mn2+ ions to perform a Fenton-like
inherent hypoxia within the TME naturally inhibits the efficacy reaction, achieving the consumption of GSH and the generation
of PDT. To enhance tumor oxygenation or mitigate hypoxia, of cOH. Moreover, it unveils the capacity for specic recognition
integrating PDT with other therapeutic strategies can be chosen and homotypic targeting of cancer cells.82
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

for a synergistic approach.77,78 The combination of chemo-

therapy and radiotherapy presents challenges like systemic
toxicity, multidrug resistance, and complications.79,80 Yet, when 3.7 Mn-based CDT and sonodynamic therapy
used in conjunction with CDT, enhancing oxygen concentration Sonodynamic therapy (SDT) is an innovative treatment
in tumor cells through the Fenton reaction and minimizing the approach that operates on a mechanism similar to photody-
distance between ROS and targets through mitochondrial tar- namic therapy (PDT). Its specic mechanism involves irradi-
geting amplies the effectiveness of PDT.78 Wang and ating target tissues with ultrasound waves. Low-frequency
colleagues developed hollow-structured manganese carbonate focused ultrasound (US) enhances the target cells' uptake
nanoparticles encapsulating the photosensitizer (chlorin e6, capacity by altering cell membrane permeability, sonolumi-
Ce6), creating a responsive nanoplatform, H-MnCO3/Ce6-PEG nescence effect, and sonothermal effect, activating sonosensi-
(HMCP NCs) (Fig. 2). HMCP NCs can upregulate intracellular tizers to gain energy and causing electron transitions. As
ROS levels through two pathways. Firstly, Ce6 can generate electrons return to their normal state, reactive oxygen species
singlet oxygen (1O2) under external laser irradiation, leading to (ROS) are produced, effectively killing the target cells.64,83 As
photodynamic therapy (PDT). Secondly, MnCO3 can specically nanomedicine progresses, there is an increasing emergence of
degrade into Mn2+ in the acidic TME and undergo a Fenton-like new multifunctional sonosensitizers based on nanoparticles,
reaction, transforming endogenous H2O2 into cOH. Using an in encompassing strategies like multifunctional nano-
vivo HeLa cell xenogra BALB/c mouse model, HMCP NCs sonosensitizing agents, comprehensive nanoplatforms, and
demonstrated signicantly enhanced therapeutic effects in combined therapeutic approaches. These new multifunctional
inhibiting tumor growth without causing apparent damage to nano-sonosensitizers typically consist of organic/inorganic
normal tissues.81 To counteract the impacts of hypoxia and GSH agents capable of generating ROS, molecules modied to
depletion on the TME and the cellular antioxidant defense enhance blood-brain barrier permeability, tumor-specic drugs
system, The biodegradable cancer cell membrane-coated mes- for accurate tumor localization, and metal ions to augment
oporous copper/silicon-manganese nanospheres (mCMSNs) magnetic resonance imaging (MRI).64,84 CDT demonstrates
designed by Liu et al. possess homotypic targeting ability for remarkable therapeutic outcomes and biosafety. Unlike
cancer cells. These nanospheres, under the synergistic inu- conventional treatments, CDT can produce ROS85 in
ence of singlet oxygen (1O2) generated and ROS produced via a controlled manner regarding time and space, with unlimited
penetration depth, targeting the high concentration of
hydrogen peroxide (H2O2) in the TME. While SDT is capable of
penetrating deep tissues, the hypoxic nature of the TME can
constrain its therapeutic impact on tumors by diminishing the
generation of ROS. The production of ROS is contingent upon
the oxygen levels within the tumor.86 The creation of Mn-based
and other metal-ion nanoplatforms for the efficacy of CDT
combined with SDT holds promising prospects and applica-
tions. Jiang and colleagues developed a MnSiO3–Pt (MP) nano-
composite. MnSiO3–Pt@BSA-Ce6 (MPBC), modied with bovine
serum albumin (BSA) and chlorin e6 (Ce6), facilitates syner-
gistic SDT and CDT (Fig. 3). Within this nanoplatform, the
photosensitizer Ce6 can produce toxic singlet oxygen (1O2)
under ultrasound irradiation. Meanwhile, platinum (Pt) loading
can catalyze the decomposition of endogenously overexpressed
H2O2 into O2, overcoming tumor hypoxia and promoting the
generation of 1O2 induced by SDT. Moreover, MP can degrade in
Fig. 2(a) Synthetic procedure for HMCP NCs. (b) The scheme of dual- the TME to release Mn2+, generating hydroxyl radicals (cOH)
mode ROS-therapeutic mechanism of HMCP NCs for combined through Fenton-like reactions for use in CDT.87 In order to
cancer treatment.81 Copyright 2019, American Chemical Society. overcome the issue of non-degradability associated with

14728 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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undue harm to normal tissues and potentially lead to resis-

tance. Moreover, the limited depth of light penetration could
mean insufficient ablation of malignant tumors beyond the
irradiated region.93 Therefore, improving PTT therapy is where
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promising therapeutic explorations are currently directed.

While manganese-based nanostructures show potential as
agents for CDT, their capability for photothermal conversion is
yet insufficient to serve as ideal agents for combined therapy.
Ma et al. developed a bifunctional Bi2−xMnxO3 nanoplatform for
synergistic PTT/CDT treatment of tumors. Doping a small
amount of bismuth (Bi) into the structure has altered the pho-
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

tothermal and CDT properties of Bi2−xMnxO3, thus enhancing

photothermal conversion efficiency and hastening the produc-
Fig. 3 Scheme of the synthesis process and therapeutic mechanism tion of cOH. The presence of reductive Mn4+ contributes to
of MPBC nanoplatform.87 Copyright 2022, Elsevier B. V. disrupting the internal redox balance in tumors by increasing
the consumption of GSH, thereby improving the effectiveness of
CDT. At the same time, a moderate photothermal effect,
traditional photosensitizers, Sun et al. developed a degradable induced by laser irradiation, can further expedite GSH deple-
perovskite-type manganese vanadate (MnVO3) photosensitizer. tion and cOH generation in the tumor vicinity, thus augmenting
Leveraging the inherent characteristics of perovskite, which the CDT impact. An evaluation of combined treatment effects
include a narrow bandgap and abundant oxygen vacancies, using a 4T1 tumor-bearing BALB/c mouse model revealed that
MnVO3 can undergo electron–hole separation and restricted the CDT/PTT synergistic treatment group showed the most
recombination induced by US, thereby enhancing the quantum favorable results.94 Moreover, Chen et al. constructed a stable
yield of ROS in SDT. Additionally, MnVO3 can degrade under spherical nanostructure based on polyethylene glycolated
acidic conditions to produce manganese and vanadium ions, manganese-doped polydopamine (PDA), PEG-PDA@Mn
leading to a Fenton-like reaction to enhance CDT efficacy. The (PP@Mn NPs) (Fig. 4). PP@Mn NPs can trigger PTT under
presence of high-valency vanadium in MnVO3 enables it to NIR light, with the released Mn2+ undergoing Fenton-like
deplete glutathione (GSH) within the TME, thus synergistically reactions to induce CDT effects. In combination with PTT,
improving the therapeutic efficacy of both SDT and CDT. they generate abundant ROS causing ferroptosis, and T1-
Crucially, the perovskite structure confers excellent biodegrad- weighted signal enhancement-mediated MRI phenomenon is
ability upon MnVO3, mitigating the prolonged presence of also observed in vivo in MFC tumor-bearing mice.90
residuals in metabolic organs aer treatment. Based on these
characteristics, in vivo experiments in 4T1 tumor-bearing mice
observed that US-assisted MnVO3 achieved good anti-tumor 3.9 Mn-based CDT and immunotherapy
effects with lower systemic toxicity,88 perfectly combining the Clinically, immunotherapy is a treatment that either suppresses
advantages of SDT and CDT treatments. or activates the immune system to treat diseases. In the context
of cancer, immunotherapy aims to bolster the immune
response against cancer cells. Generally, the former involves
3.8 Mn-based CDT and photothermal therapy systemic administration of cytokines, cancer vaccines, or
Photothermal therapy (PTT) is a non-invasive treatment adoptive cell transfer, and the latter pertains to regulating the
approach that uses photothermal conversion nanomaterials immunosuppressive TME.95 Immunotherapy is progressively
exposed to near-infrared (NIR) light irradiation to target tumor recognized as the standard approach for treating various types
sites, converting light energy into thermal energy to kill tumor of locally advanced and metastatic human cancers. However,
cells.89 Unlike radiotherapy, PTT can kill cancer cells without the overall response rate of patients to immunotherapy is still
damaging nearby normal cells. Due to its affordability, high not ideal, and combining multiple immunotherapy drugs to
efficacy, minimal invasiveness, limited side effects, and precise enhance therapeutic effects oen leads to higher toxicity.
targeting capabilities, it has attracted widespread attention in Consequently, nanomaterials can act as scaffolds or carriers,
cancer treatment.91 By using selective photothermal absorbers, amalgamating multiple drugs or treatment modalities while
minimally invasive targeted treatment of tumors that are concurrently managing various immunoregulatory pathways,
otherwise challenging to address. All laser transmission modes thereby minimizing side effects.96 Mn-based nanomaterials
aim to uniformly elevate the temperature within tumor tissues, possess a variety of functions that augment tumor immuno-
ensuring that surrounding healthy tissues remain unharmed. therapy. They are capable of directly activating cyclic GMP-AMP
For effective tumor cell ablation, photothermal damage gener- (cGAMP) synthase (cGAS), triggering the noncanonical catalytic
ally occurs when the center of the tumor temperature exceeds synthesis of 20 ,30 -cGAMP and activating the stimulator of
50 °C, creating a temperature gradient that brings the edges of interferon genes (STING). Consequently, manganese-based
the tumor to the therapeutic temperature.92 A primary concern nanomaterials demonstrate signicant potential in bolstering
with PTT is that overheating in the tumor area might cause immune responses. They aid in facilitating antigen uptake,

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Fig. 4 Scheme of the synthesis process and therapeutic mechanism of [email protected] Copyright CCBY, 2022, Informa UK Limited.

presentation, and the formation of germinal centers. This immunity, and can also serve as an immunological adjuvant for
multifaceted action renders them effective adjuvants for triple-negative breast cancer (TNBC). Manganese within CMS
immunotherapy, leveraging the body's immune system to target contributes to GSH depletion and engages in Fenton-like reac-
and eliminate tumor cells more efficiently.97 In tumor immu- tions to generate ROS, and the alteration of its mixed valence
notherapy, manganese-based nanomaterials can function as states can also lead to the occurrence of ferroptosis. Interest-
biocompatible nanocarriers for the delivery of immunothera- ingly, CMS serves as an immune adjuvant that awakens innate
peutic agents, activating the host's immune system. Addition- immunity by mitigating tumor hypoxia and activating the Mn2+-
ally, they can serve as adjuvants to adjust the tumor immune induced STING signaling pathway. This process can lead to the
microenvironment, foster immune responses, and activate the inltration of tumor-specic cytotoxic T lymphocytes (CTLs)
cGAS-STING pathway, thereby initiating tumor immuno- into tumor tissues. In bilateral 4T1 tumor-bearing BALB/c mice,
therapy.98 Combining systemic or local immunotherapy with a signicant inhibitory effect on distant tumors was observed,
traditional clinical methods has shown considerable signi- demonstrating the achievement of an anti-tumor immune
cance in the treatment of cancer. Chen and colleagues con- response.100
structed a nanocomposite based on Mn2+ and cytosine–
phosphate–guanine oligodeoxynucleotides (CpG ODN)
(MnCpGPNCs). MnCpGPNCs release Mn2+ within tumor cells to 3.10 Mn-based CDT-involved other multimodal synergistic
initiate Fenton-like reactions that generate ROS and induce cell therapy
apoptosis. They also amplify the activation of the interferon The use of a single therapeutic modality is inadequate for
gene pathway, leading to increased production of type I inter- effective tumor cell eradication.101 Leveraging the synergistic
ferons, which in turn prompts a response from various immune interplay between tumor chemodynamic therapy and two other
cells. Moreover, CpG ODN acts as an immunological adjuvant to treatment modalities allows for the optimal therapeutic
bolster antigen presentation and the potency of immune outcome with the least dosage, thereby minimizing adverse
induction. Binding of Mn2+ is shown to boost the CDT effect of effects, compared to each therapy used alone. The tri-modal
immunotherapy. In a bilateral CT26 tumor xenogra mouse synergistic therapy can be accomplished by amalgamating
model, MnCpGPNCs were observed to effectively suppress both different therapeutic agents in one nanoparticle platform.
primary and distant tumors and prevent the onset of tumors.99 For instance, Wang et al. developed a SSMID (Se@SiO2@-
Interestingly, Deng et al. developed a calcium–manganese dual- MnO2-ICG/DOX) nanocomposite (NCs) for tri-modal synergistic
ion hybrid nanostimulator (CMS), which enhances anti-tumor therapy of chemotherapy/photothermal/chemodynamic,
immunity by inducing ferroptosis and awakening innate useable for magnetic resonance imaging (Fig. 5A). SSMID

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Fig. 5 Schematic diagram of multimodal therapy of manganese-based nanomaterials: (A) scheme of the synthesis process and therapeutic
mechanism of SSMID NCs;102 copyright 2022, Elsevier B. V. (B) Schematic illustration of GOx-MnCaP-DOX applied for MRI-monitored coop-
erative cancer therapy;104 copyright 2019, American Chemical Society. (C) Scheme of the therapeutic mechanism of PBMO-GH;105 copyright
2021, Elsevier B. V. (D) Construction of PCP-Mn-DTA@GOx@1-MT and its immune stimulation capabilities.106 Copyright CCBY, 2022, Springer
Nature.

specically disintegrates in the TME with mild acidity, high multidrug resistance mechanisms. Upon US irradiation, mZMD
H2O2, and overexpressed GSH, subsequently liberating Mn2+, nanoparticles decompose within the TME. The decomposed
doxorubicin (DOX), and selenium (Se). The components within manganese dioxide undergoes glutathione oxidation reactions
such a tri-modal therapeutic nanoparticle platform each play to enhance oxidative stress. The O2 produced during this
a distinct role in safeguarding normal tissues while targeting process serves to alleviate the hypoxic conditions of the TME,
tumor cells through CDT and chemotherapy. MnO2 reacts with thereby enhancing the effect of SDT/chemotherapy. Concur-
GSH and H2O2 to produce O2 and Mn2+, alleviating tumor rently, the generated Mn2+ undergoes Fenton-like reactions to
hypoxia to bolster the efficacy of chemotherapy, and consuming yield cOH for CDT and serves as a T1-weighted MRI contrast
GSH to enhance the oxidative stress of CDT. More importantly, agent. Moreover, the released Zn2+ engage in additional redox
the released indocyanine green (ICG) can mediate the effect of reactions within the TME. Along with the ROS generated, these
photothermal therapy (PTT) under NIR laser irradiation, actions work to suppress the expression of P-glycoprotein (P-
achieving enhanced PTT/CT/CDT tri-modal therapy in gp), a key factor in the development of multidrug resistance,
conjunction with Mn2+ and DOX. The authors evaluated the thereby overcoming one of the major hurdles in effective cancer
therapeutic efficacy using an A549 tumor-bearing mouse model, treatment. Finally, in vivo experiments on HeLa tumor-bearing
nding both the anti-tumor effect and the degradation metab- nude mice conrmed that mZMD has an excellent inhibitory
olism to be favorable.102 As Mn-based nanomaterials are effect on tumors under the action of US.107
involved in oxygen production and GSH depletion, they are Besides, the combined treatment involving CDT, starvation
closely linked to ROS generation and GSH consumption, therapy, and other modalities has recently emerged as a prom-
substantially augmenting the effectiveness of oxygen-reliant inent research focus. Fu et al. ingeniously utilized an innovative
PDT or SDT.103 Guan and his team created a biodegradable in situ biomimetic mineralization technique to encapsulate
nanocomposite (mZMD) using a mesoporous zeolitic imidazo- glucose oxidase (GOx) within Mn-doped calcium phosphate
late framework loaded with MnO2 and doxorubicin hydrochlo- (MnCaP) nanoparticles, also incorporating the chemothera-
ride to facilitate synergistic SDT/CDT/chemotherapy. This effect peutic agent doxorubicin (DOX), constructing a spherical
is attained by augmenting oxidative stress and circumventing nanoparticle (Fig. 5B). This nanoparticle features

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biodegradability, strong biocompatibility, and TME pH sensi- effectiveness of immunotherapy. The assessment of anti-tumor
tivity. GOx can consume glucose within the tumor to achieve immune responses and treatment outcomes using both B16-
a “starvation” effect, while the released Mn2+ can mediate F10 and 4T1 tumor-bearing mouse models showed uniformly
Fenton-like reactions to convert H2O2 into highly toxic hydroxyl positive anti-tumor therapeutic effects.106
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radicals, achieving the purpose of CDT, and the production of In conclusion, relying solely on manganese (Mn) for CDT
gluconic acid increases the acidity of the TME, further does not yield optimal therapeutic outcomes, to enhance the
promoting the degradation of the nanoparticle platform and effectiveness of tumor treatments and simultaneously reduce
enhancing CDT. This study demonstrated that GOx-MnCaP both dosage and side effects, a signicant number of Mn-based
loaded with the anticancer drug DOX could combine ST, nanomaterials have been recently developed to be used in
Mn2+-mediated CDT and DOX-induced chemotherapy to treat conjunction with other therapeutic drugs, facilitating the
4T1 tumor-bearing mice demonstrating a substantial increase synergy of CDT with other multimodal treatments (Table 1).
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

in therapeutic efficacy compared to each single therapy.104 Future developments will also focus on a broader range of
Wang and others proposed embedding carbonyl manganese multimodal synergistic treatments associated with CDT, aiming
(MnCO) into Zr(IV)-based metal–organic frameworks (MOFs), to accomplish personalized treatment of tumors.
designing a H2O2-triggered CO gas release nanoplatform. GOx is
loaded into the porous structure of MOFs, not only the trans-
formation of intracellular glucose into H2O2, effectively severing
4 Mn-based nanotheranostics for
the energy supply to cancer cells. And the Mn2+ generated by imaging-guided CDT
MnCO undergoes a reaction with intracellular H2O2, producing
The Magnetic Resonance Imaging (MRI) guidance capability of
cytotoxic cOH, which induces apoptosis of cancer cells and
manganese-based nanomaterials, when combined with other
expedites the release of CO and energy expenditure. The use of
imaging modalities, holds broad prospects. Combining Mn-
HeLa tumor-bearing nude mice for in vivo experiments revealed
based nanomaterials with other imaging agents (CAs) enables
that this multifunctional nanoplatform effectively inhibited
MRI-based multimodal imaging-guided CDT. MRI has the
tumor growth via a synergistic effect, thus proving its capability
capability to visualize the pathophysiological hypoxic microen-
to introduce a novel approach for integrating starvation, gas,
vironment and oxygenation status at tumor sites. This not only
and chemodynamic therapies within a single material.108
contributes to the early detection of tumors but also provides
Additionally, Gu et al. investigated the efficacy of combined
real-time monitoring during the treatment of tumors.110
treatment with starvation therapy, CDT, and photothermal
therapy (Fig. 5C). They created a tumor-targeting nanoparticle
platform (PBMO-GH) by adsorbing manganese dioxide (MnO2) 4.1 Solely MRI-guided CDT
and glucose oxidase (GOD) onto Prussian Blue (PB). The enzy- Manganese-based nanomaterials possess superior MRI capa-
matic reaction catalyzed by GOD generates H2O2 and gluconic bilities and are widely used for detecting in vivo drug distribu-
acid. Simultaneously, PB can catalyze H2O2 to produce oxygen, tion, monitoring the tumor treatment process, and evaluating
continuously consuming glucose to achieve ST, and its photo- tumor treatment outcomes. Lin and others constructed meso-
thermal conversion properties enable PTT under NIR light. The porous silica nanoparticles coated with MnO2 (MS@MnO2 NPs).
Mn2+ generated from the reaction between MnO2 and GSH can This study was the rst to demonstrate that manganese dioxide
amplify CDT by producing highly toxic cOH through Fenton-like can deliver Mn2+ and deplete GSH. The MnO2 shell engages in
reactions.105 As GOx has an immune-stimulating effect, it can redox reactions with glutathione, producing Mn2+ and gluta-
not only effectively eliminate tumor cells by competitively thione disulde (GSSG). The abundant HCO3−/carbon dioxide
consuming glucose and producing cytotoxic ROS, but also (CO2) buffer in physiological culture media supports the Mn2+-
exposes tumor-associated antigens (TAAs), leading to catalyzed production of cOH. When the nanoparticles are
a comprehensive antitumor effect, and a favourable therapeutic internalized into tumor cells, the MnO2 shell can decompose,
effect is observed aer intravenous administration of MDA-MB- producing Mn2+, which undergoes Fenton-like reactions to
231 in tumor-bearing mice.109 Dai and colleagues developed generate highly toxic cOH, and deplete intracellular GSH to
a pH and ROS dual-sensitive degradable nanosystem for CDT/ inhibit the clearance of cOH. Concurrently, the dissociation of
starvation therapy/immunotherapy, which can co-deliver the MnO2 shell in response to GSH depletion can also act as
glucose oxidase (GOx) and 1-methyltryptophan (1-MT) (PCP- a regulatory mechanism for MS NPs, controlling the release of
Mn-DTA@GOx@1-MT) (Fig. 5D). The highly ROS-sensitive encapsulated drugs. Compared to MnO2, Mn2+ has a higher
degradable MOF nanoreactor can rapidly decompose within longitudinal (T1) relaxivity, with data showing a 12.8-fold
ROS-rich tumor cells, releasing Mn2+, GOx, and 1-MT. This increase in the r1 value aer GSH treatment. Aer intratumoral
minimizes the long-term retention toxicity of traditional MOFs. injection in U87MG tumor-bearing mice, the MnO2 shell can
The released GOx continuously consumes glucose to promote display the GSH-activated MRI contrast effect, which can be
H2O2 production and generate highly toxic cOH through Mn2+, used to monitor the reaction between MnO2 and GSH, as well as
leading to the complete degradation of MOF and drug release, the CDT process.111 Su et al. employed microuidic chip tech-
thereby enhancing the therapeutic effect; and it also can nology to encapsulate doxorubicin (DOX) within manganese
enhance tumor immune response and immune memory, alle- alginate nanogels, resulting in the formation of DOX@Mn-Alg.
viates tumor immune tolerance, synergistically increasing the DOX@Mn-Alg facilitates the maturation of dendritic cells (DC)

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Table 1 Summary of manganese-based chemodynamic therapy in synergy with multimodal treatment on nanoplatforms

Therapies Materials Therapeutic mechanisms Tumor model Administration Ref.

Chemodynamic TPP-DOX@MnBSA Mn2+ increases intracellular highly toxic 4T1 and MCF-7 mouse Intravenous 56
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

therapy and cOH, while DOX is used in chemotherapy. tumor xenogra, MCF-7 injection, transgenic
chemotherapy Of tumor metastasis transgenic zebrash zebrash are injected
tumor xenogra under a microscope
Chemodynamic Combined use of Fe3O4@MnO2 Both MnO2 and Fe3O4 can react with AGS tumor xenogra Intravenous injection 66
therapy and and INH endogenous H2O2 to produce highly toxic
radiotherapy cOH. The generated O2 relieves hypoxia
and improves the effect of radiotherapy
Au–MnO Janus NPs Au NPs generate reactive oxygen species Orthotopic liver tumor Intravenous injection 67
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nanovesicles under X-ray irradiation, and Mn2+ and MCF-7 tumor

undergoes a Fenton-like reaction to xenogra
generate reactive oxygen species, which
jointly enhance the RT effect
Chemodynamic Nanoselenium-coated Mn2+ undergoes a Fenton-like reaction to HeLa tumor xenogra Intravenous injection 70
therapy and manganese carbonate- generate cOH, and nano-Se activates SOD
starvation therapy deposited iron oxide to catalyze SOARs to generate H2O2, both
nanoparticle (MCDION-Se) of which inhibit the production of ATP
Chemodynamic MnS@BSA H2S is released for gas therapy, while 4T1 tumor xenogra Intravenous injection 74
therapy and gas Mn2+ generates highly toxic cOH for CDT
therapy FeCO-MnO2@MSN MnO2 generates cOH, FeCO generates 4T1 tumor xenogra Intravenous injection 75
CO, and ROS and CO can damage the
DNA and mitochondria of cancer cells
respectively
Chemodynamic H-MnCO3/Ce6-PEG (HMCP Ce6 generates singlet oxygen (1O2) under HeLa tumor xenogra Intravenous injection 81
therapy and NCs) external laser irradiation, causing PDT,
photodynamic while MnCO3 degrades into Mn2+
therapy produce highly toxic cOH
Cancer cell membrane-coated mCMSNs catalyzes the decomposition of MCF-7 tumor xenogra Intravenous injection 82
mesoporous copper/ endogenous H2O2 into O2, producing
manganese silicate toxic 1O2, and GSH triggers the
nanospheres (mCMSNs) biodegradation of mCMSNs to produce
Cu+ and Mn2+, producing cOH
Chemodynamic MnSiO3-Pt@BSA-Ce6 (MPBC) Ce6 generates 1O2 under US irradiation. U14 tumor xenogra Intratumoral 87
therapy and Pt catalyzes the decomposition of injection
sonodynamic endogenous H2O2 to generate oxygen,
therapy promotes the generation of 1O2 induced
by SDT, and Mn2+ generates hydroxyl
radical cOH
MnVO3 MnVO3 enhances the quantum yield of 4T1 tumor xenogra Intravenous injection 88
ROS. Mn2+ and vanadium ions can
consume GSH and produce Fenton-like
reaction
Chemodynamic Bi2−xMnxO3 (BM) BM has improved light heat conversion 4T1 tumor xenogra Intratumoral 94
therapy and efficiency in near infrared, and the injection
photothermal reduction of the local temperature of the
therapy restore Mn2+ and the local temperature of
the tumor area will increase the
consumption of endogenous GSH,
thereby enhancing the CDT effect
PEG-PDA@Mn (PP@Mn NPs) PDA can be used for tumor PTT, Mn2+ MFC tumor xenogra Intravenous injection 90
causes Fenton reaction to cause CDT
Chemodynamic MnCpGPNCs MnCpGPNCs release Mn2+, promoting Unilateral/bilateral Intravenous injection 99
therapy and the stimulation of the STING pathway, CT26 tumor xenogra
immunotherapy increasing the production of IFN-I to
increase the immune effect, CpG ODNs,
as an immune agent enhanced antigen
presentation and immune induction
effect
Ca & Mn dualion hybrid Mixed-valence manganese can deplete Bilateral 4T1 tumor Intratumoral 100
nanostimulator (CMS) GSH and generate ROS. Exogenous Ca2+ xenogra injection
induces mitochondrial Ca2+ overload,
GPX4 loss and LPO lead to ferroptosis
Se@SiO2@MnO2 -ICG/DOX A549 tumor xenogra Intravenous injection 102

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Table 1 (Contd. )

Therapies Materials Therapeutic mechanisms Tumor model Administration Ref.

Chemodynamic It simultaneously acts as PTT under NIR

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therapy, laser irradiation, promoting the release

chemotherapy and of Mn2+ and DOX, MnO2 reacts with GSH
photothermal and H2O2 to generate O2 and Mn2+,
therapy alleviating tumor hypoxia and initiating
CDT
Chemodynamic Mesoporous zeolitic- MnO2 can oxidize glutathione, catalyze HeLa tumor xenogra Intravenous injection 107
therapy, imidazolateframework@MnO2/ H2O2 to produce O2. Mn2+ can generate
chemotherapy and doxorubicin hydrochloride cOH, inducing CDT, and Zn2+ can
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sonodynamic (mZMD) collaboratively inhibit the expression of

therapy P-glycoprotein with generated ROS to
overcome drug resistance
Chemodynamic DOX-loaded GOx-MnCaP nano- Gox is a cofactor of starvation therapy. 4T1 tumor xenogra Intratumoral 104
therapy, therapeutic agent Mn2+-mediated Fenton-like reaction injection
chemotherapy and converts to highly toxic hydroxyl radicals
gas therapy for CDT, while DOX induces
chemotherapy
Chemodynamic Glucose oxidase (GOx) and GOx accelerates CO release and energy HeLa tumor xenogra Intravenous injection 108
therapy, starvation carbonyl manganese (MnCO) consumption. Mn2+ generated by MnCO
therapy and gas are encapsulated within UiO- can form cytotoxic cOH through
therapy 67-bpy a Fenton-like reaction
Chemodynamic GOD is loaded onto an GOD and PB can catalyze H2O2 promote MDA-MB-231 tumor Intravenous injection 105
therapy, starvation adsorbed MnO2 Prussian blue glucose consumption for starvation xenogra
therapy and (PB) nanoplatform (PBMO-GH) therapy, PB can achieve PTT under NIR
photothermal light. The Mn2+ generated from the
therapy reaction of MnO2 can produce highly
toxic cOH
Chemodynamic PCP-Mn-DTA@GOx@1-MT GOx consumes glucose and generates B16-F10 and 4T1 tumor Intravenous injection 106
therapy, starvation ROS, inducing drug release. Its activation xenogra
therapy and of tumor starvation and recruitment of
immunotherapy enhance immune response and
stimulate immune memory, while
effectively relieving immune tolerance by
blocking Ido

and enhances tumor inltration by CD8+ T cells, effectuating 4.2 Dual-modality imaging-guided CDT including MRI
immunotherapy. It also disintegrates within tumor cells due to
Multi-responsive nanoprobes hold great promise in biomedical
the acidic pH of the TME, releasing DOX to kill tumor cells. The
imaging applications, characterized by their low background and
liberated Mn2+ participates in the Fenton reaction, consistently
high sensitivity. Mn-based nanomaterials offer the capability for
supplying H2O2 to form highly toxic cOH, and the measured T1
multimodal imaging by incorporating different imaging agents
relaxivity of DOX@Mn-Alg reached 9.614 mM−1 s−1, providing
(CAs). Integrating different imaging techniques allows for the
enhanced T1-weighted MRI contrast for diagnostics in CT26 monitoring of distinct cellular and tissue states throughout
tumor-bearing mice.112 An et al. craed a multimodal nano-
tumor therapy. Modalities like positron emission tomography
material, Mn-Ti3C2@PEG, for MRI-guided thermal ablation and
(PET) can assess tumor hypoxia.110 Fluorescence imaging (FI) is
CDT. Based on linear tting, the r1 value of Mn-Ti3C2@PEG was
suitable for applications like vascular imaging, neural imaging,
calculated to be 1.05 mM−1 s−1, indicating that the magnetic
and cell tracking. Tracking tumor cells facilitates the under-
properties of the Mn component can make it serve as a T1-
standing of their metastasis and aids in surgical interventions;
weighted contrast agent for MRI with good imaging effects in
and photoacoustic imaging can effectively perform structural
reality. Additionally, it can generate highly toxic cOH through
and functional imaging of biological tissues, and can be used for
a Fenton-like reaction, and given MXene's high photothermal early detection and treatment monitoring of cancer. Combining
conversion capability and photothermal stability, it can effec-
manganese-based nanomaterials with uorescence groups can
tively inhibit tumor growth through PTT, realizing synergistic
achieve MRI/FI. For example, Li and others labeled indocyanine
therapy with PTT/CDT dual modes. The construction of 4T1
green (ICG) on manganese metal–organic framework (MOF)
tumor-bearing mice and the observation of their MRI and
nanoparticles (NPs), simultaneously loading SiOUM1, siPTPRZ1,
photothermal imaging indicated favorable anti-tumor treat-
and cisplatin, and linking with arginine–glycine–aspartic acid
ment outcomes.113
(RGD) peptide. This realizes targeted therapy mediated by siRNA

14734 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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interference, enhancing cisplatin treatment and CDT. When computed tomography (CT) scan. Combining manganese-
injected into subcutaneous OCM1-tumor-bearing BALB/c nude based nanomaterials with Au NPs can also easily achieve MRI/
mice, this nanomaterial enables the observation of time- CT. Sha et al. in situ doped metal manganese onto gold core
dependent biodistribution and a lung metastasis model in the mesoporous silica nanoparticles to create Au@MMSN.
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

tumor-bearing mice via bioluminescence imaging (Fig. 6). And Following this, they further modied Au@MMSN with sodium
the FI capability facilitates the real-time monitoring of its in vivo alendronate (Ald), and loading doxorubicin (DOX) onto
distribution. This nanosystem provides an approach for preci- Au@MMSN-Ald, it demonstrated effective osteosarcoma tar-
sion drug delivery in treating tumors, endowed with dual-modal geting capabilities. The resultant DOX@Au@MMSN-Ald
imaging capabilities.55 Numerous studies have proven the possesses dual-modal CT/MR imaging capabilities and
application of PT imaging. Zhu and others constructed a multi- features combined chemotherapy/CDT properties. Hence, in
functional intelligent nanoparticle platform MnFe-LDH/ certain TME, DOX@Au@MMSN-Ald releases gold nanoparticles
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

MTX@GOx@Ta (MMGT) for MRI/photothermal (PT) dual- from the core and Mn2+ from the shell, which are respectively
modal imaging-guided CDT/chemotherapy dual-modal therapy, validated in CT and MR dual-modal imaging, evidencing the
with self-supplied H2O2 and enhanced photothermal effects. efficient accumulation of Au@MMSN-Ald at tumor locations.
Through a simple hydrothermal reaction, MnFe-LDH (M) was The manganese ions and DOX can mediate CDT and chemo-
synthesized and subsequently loaded with the methotrexate therapy respectively. Intratumoral injection of
(MTX). Then, glucose oxidase (GOx) and tannic acid (Ta) are DOX@Au@MMSN-Ald in situ 143B tumor-bearing mice can
modied separately to assemble MMGT. MMGT degrades within clearly display tumor site images, while intravenous adminis-
the tumor microenvironment to generate Mn2+/Fe3+, GOx, and tration allows for tracking of Mn2+ release and monitoring of
MTX. Mn2+/Fe3+ and MTX are capable of transforming endoge- the in vivo CDT process. All in all, the producted
nous H2O2 into cOH via the Fenton reaction and chemotherapy, DOX@Au@MMSN-Ald nanoparticles, with their imaging guid-
facilitating combined CDT. Furthermore, in vitro experiments ance and combined treatment advantages, also exhibited
demonstrated that in PBS solution at pH 5 with 10 mM glucose, excellent therapeutic effects in eliminating cancer cells and
the MMGT r1 value increased to 1.24 mM−1 s−1, indicating that inhibiting osteosarcoma growth.115
Mn2+ enhances the T1-MRI contrast signal. And the released GOx
was able to consume glucose and provide H2O2, thereby allevi- 4.3 Multimodal imaging-guided CDT including MRI
ating constraints on CDT. MnFe-LDH is capable of transforming
In the pursuit of improved imaging precision, precise diag-
NIR light energy into thermal energy, facilitating PT imaging and
nostics, and enriched information, integrating Mn-based
simultaneously boosting the efficacy of CDT. Aer intravenous
nanomaterials with multifunctional nanoprobes for tumor
injection, the PT imaging results showed the temperature
multimodal imaging-guided CDT is effective. NIR-II semi-
changes of the tumor at different time points, the T1-weighted
conductor polymers are excellent photothermal agents capable
MR images revealed that MMGT accumulated in the tumor tissue
of effectively absorbing NIR-II light and converting it into
and successfully degraded into Mn2+, with a good contrast
thermal energy to mediate PTT and kill tumor cells. This NIR-II
effect.114
absorption capability can be utilized to achieve efficient PTT
Gold nanoparticles (AuNPs) can serve not only as photo-
guided by NIR-II photoacoustic imaging. Utilizing this feature,
acoustic imaging agents and are widely used in long-term
Dai and colleagues engineered NIR-II phototherapeutic nano-

Fig. 6 Pharmacokinetics and targeting effect and tumor suppression effects of intravenously injected NPs in vivo. (A) In vivo real-time biolu-
minescence imaging of UM tumor-bearing mice at different time points after administration of ICG-COP@MOF-PR; (B) ICG fluorescent
intensities from ex vivo imaging of the major organs, and the tumors 24 h after injecting ICG-COP@MOF-PR; (C) T1-weighted MRI after
intravenous injection with ICG-COP@MOF-PR at predesigned time points; (D and E) the tumor growth curves and bioluminescence imaging
showed UM growth with different treatments in vivo.55 Copyright CCBY, 2023, Springer Nature.

© 2024 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2024, 14, 14722–14741 | 14735
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adjuvants (PMR NAs) by coordinating Mn2+ with ultrasmall photosensitizer indocyanine green (ICG) onto Cu/Zn-metal–
NIR-II semiconductor polymer dots and toll-like receptor organic frameworks (MOF), culminating in the formation of
agonists (R848). PMR NAs disintegrate in response to the ICG@Mn/Cu/Zn-MOF@MnO2. Cu2+ and MnO2 reacted with
acidic TME, and the disintegrated ultrasmall NIR-II semi- GSH to reduce ROS depletion and produce Mn2+ that mediates
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conductor polymers synergize with laser irradiation for PTT MRI and was calculated to have an r1 value of 7.91 mM−1 s−1,
within the tumor and can be used for PT imaging, with their showing a good MR signal. Concurrently, Cu+ and Mn2+
inherent uorescence allowing for FI as well. The released partake in a Fenton-like reaction, generating cOH to trigger
Mn2+ can mediate a Fenton-like reaction to induce CDT. Its T1- CDT. The released ICG can mediate PTT and PT imaging under
weighted MR signal was observed to increase with concentra- laser irradiation, and upon release at the tumor site, it can
tion, yielding an r1 value of 5.68 mM−1 s−1, thereby enhancing enable “switched-on” FLI. In U87 tumor-bearing nude mice,
the MRI effect (Fig. 7). The synergistic therapy of CDT/PTT can intravenous injection of ICG@Mn/Cu/Zn-MOF@MnO2 fol-
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

induce anti-tumor immunity through the ICD effect and, in lowed by laser irradiation showed rapid temperature increases
conjunction with the simultaneously released R848, enhances at the tumor site in PT imaging results, reaching up to 56 °C
the anti-tumor immune response. In vivo experiments using within 10 minutes, sufficient to ablate the tumor. The eman-
the B16F10 bilaterally tumor-bearing mice model to validate cipation of Mn2+ amplies tumor-specic MRI signals, sug-
the anti-tumor effect demonstrated that PMR NAs have gesting the drug's effective accumulation within the tumor.
a multilevel tumor-killing effect, which can be used for precise And the liberation of ICG post-injection manifests
diagnosis of deep-seated tumors and amplication of anti- a pronounced ndings.117
tumor immunotherapy.116 The integration of uorescent Apart from the combined use with uorescent molecules, the
molecules is a widely recognized strategy for multimodal co-application of Mn2+-mediated T1-weighted MR imaging and
imaging, an approach also employed by Cheng and others, T2 CAs can be used to improve the efficiency of MR imaging. Tao
they consistently integrated Mn2+, MnO2, and the et al. incorporated Mn into the blue dye Prussian Blue (PB),

Fig. 7 In vivo multimodal imaging. (A) NIR-II FI of whole-body blood vessels of nude mice injected with PMR NAs solution via the tail vein.
Fluorescence intensity profiles of the cross-sectional lines from (B) magnified abdominal vascular image and (C) magnified femoral vascular
image. (D) NIR-II FI of B16F10 tumor-bearing mice injected with PMR NAs solution. (E) Mean fluorescence intensity in the tumor region. (F) PAI
and (G) mean PA intensity of tumors from mice injected with PMR NAs solution. Scale bar: 3.5 mm. (H) MRI of cross-sections of mice and (I) mean
MR signals of tumors after injection with PMR NAs.116 Copyright 2023, Elsevier Ltd.

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which is used for T1 and T2-weighted MR imaging contrast 5 Opportunities and challenges
agents, to create MnPB NPs, which induce PTT when irradiated
by lasers within the NIR spectrum, with their anti-tumor effects Overall, Mn-based CDT therapies have achieved considerable
observable via photoacoustic imaging. Moreover, the incorpo- advancements. Although there have been achievements, this
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ration of Mn allows MnPB NPs to engage in Fenton-like reac- domain continues to encounter a myriad of opportunities and
tions, instigating CDT, while the r1 and r2 values of MnPB NPs challenges. To foster the progress and clinical translation of
were detected to be 0.6693 mM−1 s−1 and 9.379 mM−1 s−1, both Mn-based CDT therapy in oncology, future research should
of which were signicantly higher than the r1 and r2 values of adopt a multi-faceted approach, focusing on aspects such as
pure PB NPs, indicating that the combination of Mn and PB material fabrication, performance investigation, mechanism
could enhance MR imaging. Post intravenous injection into elucidation, and assessment of biological efficacy.
Skov-3 tumor-bearing mice, tri-modal in vivo imaging validated Firstly, developing simple and highly reproducible synthesis
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

the formidable efficacy of MnPB NPs in tumor therapy.118 methods is crucial for promoting the biological application of
In summary, manganese-based nanomaterials, as ideal MRI Mn-based nanomaterials. The biocompatibility of Mn-based
contrast agents (CAs), have great potential in MRI-guided tumor nanomaterials is indeed a crucial factor for their successful
therapy (Table 2). For augmented imaging accuracy, combining clinical translation. Recent advancements in biomimetic
Mn-based nanomaterials with other contrast agents, facilitates mineralization strategies have been particularly effective in
the effortless attainment of multimodal imaging associated producing Mn-based nanomaterials with enhanced biocom-
with MRI using the prepared Mn-based nanomaterials. patibility, and it became the preferred method for preparing

Table 2 Manganese-based multi-modal imaging-guided chemodynamic therapy involving MRI

Imaging Tumor
Category modality Contrast agents Materials Imaging principles model Administration Ref.

Single Magnetic Mn2+ MS@MnO2NPs Mn2+ exhibits a higher U87MG Intratumoral 111
modal resonance longitudinal (T1) relaxation rate
tumor injection
imaging imaging (MRI) xenogra
Mn2+ DOX@Mn-Alg Providing enhanced T1-weighted CT26 Intravenous 112
MRI contrast for diagnosis tumor injection
xenogra
Mn2+ Mn-Ti3C2@PEG The magnetic properties of the 4T1 tumor Intravenous 113
Mn component allow it to serve as xenogra injection
a T1-weighted contrast agent for
MRI
Dual-modal MRI and ICG/Mn2+ ICG-COP@MOF-PR ICG conducts FI through its OCM1 Intravenous 55
imaging uorescence intrinsic uorescence, while tumor injection
imaging (FI) manganese holds the potential for xenogra
MRI and possesses dual-modal
imaging capabilities
MRI and Fe3+/Mn2+ MnFe-LDH/MTX@GOx@Ta Mn2+ can enhance T1-MRI 4T1 tumor Intravenous 114
photothermal (MMGT) contrast signals, while MnFe-LDH xenogra injection
(PT) can convert NIR light energy into
heat for PTI
MRI and Au NPs/Mn2+ DOX@Au@MMSN-Ald Gold nanoparticles and Orthotopic Intratumoral 115
computed manganese ions within the shell 143B injection
tomography can provide dual-modal imaging tumor
(CT) scan in both CT and MRI
Multimodal MRI, Mn2+/NIR-II The self-assembly of ultrasmall Ultra-small NIR-II semiconductor B16F10 Intravenous 116
imaging uorescence semiconductor NIR-II semiconducting polymer polymers for PAI, which also bilateral injection
imaging and polymer dots and the toll-like receptor exhibit intrinsic uorescence for xenogra
photoacoustic agonist resiquimod (R848) FI. The released Mn2+ can be used tumor
imaging utilizing Mn2+ as coordination for MRI
nodes (PMR NAs)
MRI, ICG/Mn2+ ICG@Mn/Cu/Zn-MOF@MnO2 Released Mn2+ can be used for U87 tumor Intravenous 117
uorescence MRI. ICG can mediate both PAI xenogra injection
imaging and and FI under laser irradiation
photothermal
Other (T1/T2) MRI PB/Mn2+ MnPB NPs PB and Mn2+ serve as contrast Skov-3 Intravenous 118
imaging and agents, facilitating the combined tumor injection
photoacoustic use of T1-weighted MR imaging xenogra
imaging and T2 contrast agents to enhance
MR imaging efficiency

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Mn-based nanomaterials.119 Moreover, the surface properties of Simultaneously, enhancing the targeted delivery of Mn-based
nanomaterials have a signicant impact on their behavior nanomaterials can maximize the bioavailability of nano-
within biological systems. Therefore, by nely modifying the medicine at specic sites and times. Such targeted nano-
surface properties of Mn-based nanomaterials, their targeting medicines not only help reduce the dosage but also minimize
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

to lesion sites can be signicantly enhanced, improving their the side effects of the drugs, thereby increasing biosafety.122
drug delivery efficiency. This not only enhances the therapeutic Currently, the biosafety assessment of Mn-based nanomaterials
effect of CDT but also helps to improve the efficacy of other largely relies on in vitro cell viability tests,123 and in order to
treatments like chemotherapy and reduces side effects, making accelerate the translation to clinical applications, future studies
the treatment process safer and more effective. In general, the should not be limited to small animal models (e.g., mice, rats),
research and application horizons of Mn-based CDT therapy are but also large animal models (e.g., monkeys) can be constructed
extensive. However, systematic and comprehensive research is to comprehensively assess the biosafety and efficacy of Mn-
Open Access Article. Published on 07 May 2024. Downloaded on 1/15/2025 8:49:30 AM.

still necessary to further elevate its therapeutic efficiency and based nanoplatforms. Such research can not only provide
clinical viability, thereby optimally serving tumor therapy. more in-depth biosafety data but also reveal potential biological
Secondly, further research into the ROS generation mech- effects and mechanisms, offering a more solid scientic foun-
anism underpinning CDT of Mn-based nanomaterials is dation for clinical applications. Additionally, the MRI imaging-
crucial for steering the development of multifunctional guided feature of Mn-based nanomaterials is critically impor-
manganese-based nano-platforms. While ROS generation via tant for monitoring drug metabolic pathways and tissue
Fenton/Fenton-like reactions has been thoroughly investi- distribution throughout the treatment process. These studies
gated, however, the principles of classical catalytic chemistry will assist in understanding the behavior of drugs in the body,
may not adequately apply to intricate physiological contexts. how they interact with biological systems, and how to optimize
An enhanced comprehension of the CDT process within living dosing and administration strategies, to maximize therapeutic
organisms could improve the efficacy of CDT and address effects, minimize side effects, and provide important insights
challenges such as the scarcity of H2O2 and low pH levels in the for their clinical translation. In summary, based on their
TME. Besides thoroughly researching mechanisms related to biosafety and biological performance assessment, Mn-based
tumor therapy based on the Fenton reaction, it's also essential CDT therapies are highly likely to pave a promising path in
to delve into ROS generation mechanisms based on non- the eld of nanomedicine, offering new strategies for tumor
Fenton reactions. It's critical for the development of effective therapy.
Mn-based nanotherapeutic platforms to extensively study
various CDT mechanisms and their synergistic interactions 6 Conclusions
with other treatment modalities.120 This involves not just
studying their behavior in various tumor microenvironments, Manganese is a trace element crucial for human health,
but also how to enhance therapeutic outcomes by manipu- participating in and playing a signicant role in various
lating the TME or other biological processes, and how to physiological processes. Particularly in the eld of nano-
integrate them with other treatment strategies (such as medicine, manganese exhibits unique functions, such as
chemotherapy, radiotherapy, etc.) to achieve a comprehensive applications in immune defense, chemodynamic therapy
attack on tumors. A comprehensive grasp and application- (CDT), magnetic resonance imaging (MRI), and tumor micro-
oriented research into the anti-tumor mechanisms of Mn- environment (TME) modulation. Among these applications,
based nanomaterials not only aids in devising more effica- the CDT and immune defense capabilities contribute to the
cious tumor treatment strategies but also establishes a robust combined application of CDT and im-munotherapy, while
foundation for the clinical transition and application of Mn- TME modulation can enhance the effects of tumor therapy.
based nanomaterials. The MRI capability is utilized to monitor the progression of
Finally, comprehensive investigation into the biocompati- tumor therapy. Hence, Mn-based nano-platforms emerge as
bility and biosafety of Mn-based nano-platforms is vital for their optimal choices for tumor therapy tracking. In tumor CDT,
clinical conversion. This primarily includes, but is not limited Mn-based nanomaterials are extensively used not only as nano-
to, research on cytotoxicity, hemocompatibility, tissue compat- carriers for drug delivery to tumor sites, but manganese ions
ibility, immunogenicity, and pharmacokinetics. A comprehen- also serve as important components within the nanomaterials,
sive assessment of Mn-based nano-platforms remains participating in tumor therapy. However, due to the hetero-
indispensable before advancing to clinical applications. geneity and complexity of tumors, the effectiveness of single
Although preliminary results indicate that Mn-based nano- Mn-based CDT may be limited. Recognizing this challenge,
materials exhibit good biocompatibility during treatment, the recent years have seen the development of multimodal syner-
strong oxidative effect of manganese ions poses serious side gistic therapy strategies aimed at enhancing therapeutic
effects to the liver and kidneys.46 Moreover, the low bioavail- outcomes while reducing drug side effects, involving the use of
ability and low degradation rate of free manganese ions present manganese-based nanomaterials combined with a variety of
long-term toxicity issues to the human body. Therefore, devel- therapeutic drugs. Manganese-based nanomaterials indeed
oping ultra-small or biodegradable Mn-based nanomaterials is show signicant promise in the creation of multifunctional
a favorable approach to achieving rapid metabolism and elim- nanoprobe systems, which combine MRI with other imaging
ination from the body, thereby enhancing biosafety.121 methods and can be used to monitor the tumor treatment

14738 | RSC Adv., 2024, 14, 14722–14741 © 2024 The Author(s). Published by the Royal Society of Chemistry
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This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

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