Advances in the application of manganese dioxide and its composites for theranostics

Abstract

Manganese dioxide (MnO₂), a type of redox-active transition-metal dioxide, has found wide applications in catalysts, oxidants, ferrites, achromats and battery materials. In addition, MnO₂ is also increasingly being used in the biomedical field for disease diagnosis and treatment. Despite its great potential, there are limited articles that comprehensively review the use of MnO₂ in disease diagnosis and treatment. This review provides a concise overview of the latest developments in MnO₂ nanomaterials, focusing on their applications as magnetic resonance, photoacoustic and fluorescent contrast agents. We first summarize the preparation methods of MnO₂ nanomaterials and the mechanisms by which they serve as magnetic resonance contrast agents. We then briefly introduce their applications as photoacoustic and fluorescent contrast agents. Finally, we provide an overview of the therapeutic applications of MnO₂ nanomaterials and discuss the challenges and prospects for their future clinical applications.

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Min Wu

Min Wu is currently an associate professor of the Huaxi MR Research Center (HMRRC), Department of Radiology, at the West China Hospital of Sichuan University in China. She received her PhD degree in biochemistry and molecular biology from the Institute of Nanobiomedical Technology and Membrane Biology, West China Hospital of Sichuan University, in China in 2010 under the supervision of Professor Xiaojun Zhao. Her research focuses on the synthesis of contrast agents/drug delivery systems and their application in small animals to reveal cancer mechanisms and for theranostics.

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1. Introduction

Manganese dioxide (MnO₂) is one of the most interesting inorganic compounds due to its excellent physicochemical properties (high oxidation, light absorption capabilities).^1,2 Recently, it has been prepared in a variety of forms, such as nanodots,³ nanorods/fibers,⁴ nanosheets,⁵ mesopores/molecular sieves,⁶ branched structures⁷ and aggregates/flowers,⁸ and widely used in catalysts,^9,10 oxidants,¹¹ ferrites,^12,13 achromats¹⁴ and battery materials.^15,16 It is also used in disease diagnosis and treatment. Molecular imaging techniques (MITs) have garnered significant attention since the early 1990s due to their non-invasive ability to visualize molecular-level processes, shedding light on the underlying biological mechanisms of diseases.¹⁷ Molecular imaging is a valuable method in disease diagnosis to assess metabolic changes and detect disease progression. With rapid advancements in nanotechnology, MITs including photoacoustic imaging (PA),¹⁸ fluorescence (FL) imaging,¹⁹ single-photon emission computed tomography,²⁰ optical microscopy,²¹ positron emission computed tomography²² and magnetic resonance imaging (MRI),²³ have attracted significant attention based on nanometer-scale contrast agents. Among them, MRI contrast agents can provide anatomical structures and pathology with a high spatial resolution,^24–26 these agents are used in the fields of inflammation detection,²⁷ fibrosis diagnosis,²⁸ thromboembolic disease imaging²⁹ and cancer therapy.³⁰ Furthermore, the role of photoacoustic imaging and fluorescence imaging in disease diagnosis is paramount.

MnO₂ has been extensively investigated as a potential magnetic resonance contrast agent, exhibiting promising results for T₁, T₂ and T₁–T₂ dual contrast enhancements. Gadolinium (Gd) chelates³¹ and superparamagnetic iron oxide (SPIO)³² are the most commonly employed clinical contrast agents for magnetic resonance imaging. However, several investigations have demonstrated that Gd-based contrast agents increase patients’ risk of developing nephrogenic systemic fibrosis and have the potential to deposit in various tissues, including the brain, bone and skin, even in patients with normal kidney function.^33,34 In comparison with Gd and SPIO contrast agents, Mn-based contrast agents offer distinct advantages: (1) They come in various forms, such as oxides, nanoparticles and chelates. (2) Even a small amount of Mn²⁺ has a robust ability to alter the signals in MRI, resulting in substantial contrast enhancements. (3) Mn²⁺ contrast agents exhibit low toxicity, because manganese is a crucial trace element in the human body and biological regulatory systems effectively maintain its homeostasis.³⁵ Manganese is a naturally occurring element that serves as an essential component of cells and mitochondria, playing a vital role in cellular and mitochondrial functions simultaneously. It has been confirmed that minimal quantities of manganese residues pose lower risks to human health, as the body has the function to maintain metal homeostasis and eliminate excess manganese or incorporate it into the body's manganese pool. (4) Mn²⁺ contrast agents can be used in neuroimaging. Above all, owing to its excellent biocompatibility and remarkable optical–physical properties,³⁶ biogenic Mn(II) has been extensively investigated as a T₁ contrast agent.³⁷ However, there have been several recent studies that have started to investigate MnO₂ as a contrast agent for both T₂ and T₁–T₂ dual contrast.

Except for MR contrast agents, studies have demonstrated that MnO₂ nanomaterials can also serve as contrast agents for FL imaging³⁸ and PA imaging.³⁹ FL imaging is a technique that takes advantage of the luminescence properties of fluorescent molecules to visualize living organisms. Alternatively, PA imaging is a method that uses the photoacoustic signal generated by biological tissues to provide information about their light absorption properties.⁴⁰ More specifically, PA imaging is a technique that enables the detection of photoacoustic signals by visualizing the distribution of light absorption in tissues. When combined with MRI, these imaging modalities can offer a more precise diagnosis of diseases and aid in subsequent treatment strategies.⁴¹

Due to the significant potential of MnO₂ for imaging, extensive articles have been published, with numerous innovative ideas being put forward for subsequent clinical translation. This review provides a comprehensive summary of MnO₂ nanomaterial synthesis methods, their principles as MRI contrast agents, their applications in diagnosing various diseases and their therapeutic potential. Additionally, the review briefly introduces the use of MnO₂ nanomaterials as photoacoustic and fluorescent contrast agents (Fig. 1). Finally, we present our opinions on potential future directions for research in this field. In summary, MnO₂ nanomaterials are widely used as contrast agents and therapeutic drugs, offering valuable insights for their incorporation into diagnosis and treatment strategies.

Fig. 1 A schematic illustration of the imaging principle, preparation methods, imaging applications and treatment strategies for MnO₂ nanomaterials (from center to periphery).

2. Preparation of MnO₂

In recent years, numerous approaches have been developed for the synthesis of MnO₂ nanomaterials. These approaches have resulted in the successful production of various forms of MnO₂, including nanowires, one-dimensional nanodots, two-dimensional nanosheets, multidimensional nanocubes, flower-like structures and hollow spheres.^42–45 In summary, the primary approaches for the synthesis of MnO₂ nanomaterials are the biomineralization method, the template method and the redox method.

Biomineralization is a promising technique for combining biomolecules with inorganic substances (Fig. 2a).^46–48 Specifically, it produces inorganic minerals by modulating biomolecules.^49,50 This process involves the controlled conversion of ions under physicochemical conditions to transform bio-organic materials, such as serum albumin, into solid minerals.⁵¹ Then bio-organic materials can function as nucleating agents, co-regulators or mineral ion templates that influence the composition and characteristics of inorganic materials.⁵² In the preparation of MnO₂, bio-organic materials are introduced to guide Mn²⁺ nucleation, which then spontaneously forms MnO₂via oxidation or growth in alkaline solutions. Additionally, MnO₂ can be combined with bio-organic materials such as serum albumin (HSA)⁵³ and genetically engineered proteins⁵⁴ for imaging purposes. Overall, this approach is one of the most effective strategies due to its economical, convenient and environmentally friendly advantages. However, biomineralization processes involve the use of living organisms, such as bacteria or fungi, to precipitate minerals like MnO₂. Controlling the reaction conditions to achieve consistent results is challenging due to the complexity of biological systems and these methods may have a lower efficiency and yield compared to conventional chemical synthesis routes.

Fig. 2 Preparation of MnO₂. (a) Synthesis of MnO₂ nanomaterials by biomineralization.⁴⁶ Copyright 2018, American Chemical Society. (b) Synthesis of MnO₂ nanoparticles by the template method, including the soft template method and the hard template method.⁶³ Copyright 2020, Royal Society of Chemistry. (c) Synthesis of MnO₂ nanomaterials by the redox method.

The template method is a versatile technique that can be used to produce nanoparticles with various structures.⁵⁵ The templates used can be made of any materials with nanostructures.⁵⁶ The process typically involves three steps: creating templates, preparing MnO₂ according to the templates and removing or not removing the template agent as necessary.⁵⁷ Furthermore, the template method can be categorized into two types based on the type of template used: soft templates and hard templates.⁵⁸

Soft templates, which include block copolymers, flexible organic compounds and surfactants, function as structure-directing agents.^59,60 The soft template method results in micelles with diverse morphologies depending on the concentration of soft templates. The micelle structures enable inorganic materials to exhibit distribution trends driven by van der Waals forces, hydrogen bonds and electrostatic interactions between surfactant molecules and nanomaterials. This method is advantageous due to its simplicity of operation and the ability to produce materials with various forms. However, the soft template method has limited control over the shape, size and homogeneity of the nanoparticles.

In contrast, the majority of hard templates maintained by covalent bonding are polymer⁶¹ and metal templates.⁶² The hard template method is effective at reducing interference since it does not involve surfactants. Furthermore, this method enables precise control over the size and morphology of the nanomaterials, resulting in a high degree of stability. However, the nanomaterials produced by the hard template method have a simple structure with fewer morphological varieties. Consequently, this method is the preferred approach for producing shell-like MnO₂ nanomaterials (Fig. 2b).⁶³ Certainly, the template method also has certain limitations. The template method relies on the use of a specific template material to guide the growth of MnO₂, which limits the structural diversity. The resulting MnO₂ structure tends to replicate the morphology of the template, making it challenging to obtain a wide range of structures using this method.

Additionally, the redox method has become a common approach for synthesizing MnO₂ due to its efficiency and convenience.⁶⁴ The Mn⁷⁺ (KMnO₄) redox method is particularly popular among redox techniques because of its effectiveness. Potassium permanganate (KMnO₄), a powerful oxidizing agent, can react with certain reducing agents to produce MnO₂, similar to small organic molecules, polymers and proteins.^65,66 Another redox method is the Mn²⁺ (MnCl₂) oxidation method. For instance, Zhang et al.⁶⁷ employed a reaction between KMnO₄ and H₂O₂ to generate ultra-small MnO₂ (sMnO₂) nanosheets (Fig. 2c). Overall, the redox method offers benefits such as a rapid process, low cost, mild synthesis conditions, energy efficiency and diverse applications in the biomedical fields.⁶³ Nevertheless, the redox method can result in inhomogeneous formations and the possibility of the formation of impurities or side products of MnO₂, which makes it difficult to mass produce.

3. MnO₂ for magnetic resonance imaging

3.1 The mechanism of MnO₂ as a contrast agent

MRI contrast agents alter the relaxation of tissues to increase the sensitivity and specificity of diagnostic images.⁶⁸ Recently, numerous studies have shown that manganese contrast agents could serve as T₁, T₂ and T₁–T₂ dual contrast agents, and their mechanisms are briefly summarized as follows.

3.1.1 The mechanism of MnO₂ as a T₁ contrast agent. Brownian motion of a paramagnetic substance generates a fluctuating magnetic field that accelerates the relaxation of protons in the surrounding tissue. The time required for the magnetization of protons to return to their initial state after excitation is referred to as the T₁ relaxation time constant. The changes in T₁ relaxation time are due to excess energy released by the excited proton being transferred to surrounding tissues. T₁-Based MRI contrast agents could reduce the T₁ relaxation time, resulting in higher signal intensities in T₁-weighted MR images and thus T₁ contrast agents are called “positive contrast agents”.⁶⁹ Mn(II)⁷⁰ and Gd(III)⁷¹ are the most common MR contrast agents, thus improving proton relaxation and leading to high signals in T₁-weighted imaging.⁷⁰ The T₁ relaxation rate depends on the spin quantum number (S) and is inversely proportional to the distance between the metal ion and the water proton.⁷²

Mn(II) is the critical element in MnO₂ nanoparticles for magnetic resonance enhancement imaging. Coordinating Mn atoms with six oxygen atoms in an octahedral geometry while keeping them isolated from an aqueous environment can induce changes in the longitudinal or transverse relaxation of protons. MnO₂ nanoparticles can be reduced to Mn(II) by intracellular reducing substances, such as glutathione (GSH) and hydrogen peroxide (H₂O₂). Two properties of Mn(II) determine its ability to act as a MRI contrast agent: (1) with five unpaired electrons in the ground state, it has a considerable degree of paramagnetism (Fig. 3a);⁷⁰ (2) the inner layer and the outer layer of water molecules undergo rapid dissociative exchange (Fig. 3b and c).⁷³ One crucial point to consider is that one or more water molecules can be located inside the Mn(II) inner coordination sphere in aqueous biological media. The coordination water molecules are unstable in this context since the Mn–O bond weakens in the high-spin Mn(II) ligand field caused by the interaction with two three-dimensional sigma antibonding electrons.⁷⁴ The findings demonstrate that the inner sphere in Mn undergoes hydrolytic dissociation with relative ease and the exchange of water between the inner sphere and the medium happens very quickly, in the submicrosecond range.⁷⁵ As a result, MRI shows high spin Mn(II). In light of this, many Mn-based contrast agents have been developed and are particularly effective at enhancing the contrast of T₁-weighted images.^76–78

Fig. 3 Manganese properties. (a) Diagram of the ligand field energy levels for the [Mn(H₂O)₆]²⁺ electronic structure. (b) The inner coordination sphere contains six water molecules in an octahedral configuration. (c) Aquo complex water exchange rate constants, unchelated Gd³⁺ (red writing) has a somewhat greater rate of water exchange than Mn²⁺ (arrow), which is in the submicrosecond range. Water exchange for chelated Mn(II) ranges from 10⁶ to 10⁷ s⁻¹.⁷³ Copyright 2010, Royal Society of Chemistry.

3.1.2 The mechanism of MnO₂ as a T₂ contrast agent. T ₂ relaxation, also known as spin–spin relaxation, refers to the decay of transverse magnetization of tissue after it has been excited by an external radiofrequency.⁷⁹T₂ relaxation originates from interactions between spins within tissues. These interactions can arise from a variety of sources, including dipole–dipole interactions, chemical shift interactions and interactions with other nearby spins.⁸⁰ These interactions cause the individual spins to experience slightly different magnetic fields, leading to a spread in their precession frequencies. As a result of this frequency spread, the phase coherence among the spins is gradually lost over time. The loss of phase coherence causes the transverse magnetization to decay exponentially with a characteristic time constant called T₂. The T₂ relaxation time is influenced by various factors, such as molecular motion, molecular interactions and magnetic field inhomogeneities.

The T₂ contrast agent reduces the signal by dephasing the surrounding protons’ spin in bulk water, which leads to a decrease in signal intensities.⁸¹ The rate constant linked to the T₂ relaxation time is defined as 1/T₂. MnO₂ can be used as a T₂ contrast agent in MRI. T₂ contrast agents are substances that alter the relaxation times of nearby water protons, leading to contrast enhancement of T₂-weighted MR images.⁸² The manganese ions included in MnO₂ nanoparticles have paramagnetism originating from unpaired electrons. Paramagnetic substances generate local magnetic fields, which could dephase the spins of water protons and thus accelerate their T₂ relaxation. Furthermore, MnO₂ nanoparticles have a porous structure, which could contribute to an additional mechanism to accelerate the T₂ relaxation of water protons. Specifically, pores on the nanoparticles could restrict the diffusion of water molecules, which would lead to increased interactions between water protons and the MnO₂ nanoparticles and thus further enhance the T₂ relaxation.⁸³

K. Deka et al.⁸⁴ investigated manganese oxide nanoparticles infused in mesoporous three-dimensional carbon frames as MRI contrast agents. Their research revealed a remarkable increase in T₂ contrast by controlling the interaction between magnetic ions and water (Fig. 4a). Meanwhile, Zhu et al.⁸⁵ developed a hydrogel-based drug-carrying system to prevent postoperative tumor recurrence. KMnO₄ was used as the oxidizing agent to prepare the CMC-DAMnO₂/MnO hydrogel. In the hydrogel, KMnO₄ is not only used as an oxidant to trigger the polymerization and gelation of CMC-DA but is also transformed into MnO₂ and MnO to afford the T₂-weighted MRI agent to realize tumor visualization. In addition, researchers have used the T₂ attenuation of MnO₂ to design a nanoprobe for directly determining alkaline phosphatase (ALP) in blood.⁸⁶ In the presence of ALP, 2-phospho-L-ascorbic acid trisodium salt was catalyzed to produce ascorbic acid, which reduced MnO₂ to Mn²⁺, causing T₂ decay. This research is another application of MnO₂ as a T₂ contrast agent.

Fig. 4 (a) T₂-Weighted in vitro MR images of aqueous dispersions of the Mn₂O₃@CF nanosystem with various Mn concentrations.⁸⁴ Copyright 2020, Elsevier. (b) PBMn can be used as a PAI/T₁/T₂ triple mode contrast agent, in image-guided PTT, and in oxygen regulation of breast cancer grafts in vitro.⁹⁵ Copyright 2017, American Chemical Society. (c) MnO₂ is metabolized by the kidneys.

3.1.3 The mechanism of MnO₂ as a T₁–T₂ contrast agent. MnO₂ is traditionally used in T₁ magnetic resonance enhanced imaging.⁸⁷ Moreover, researchers have demonstrated that MnO₂ can serve as a T₁–T₂ dual contrast agent for tumor MRI.⁸⁸ MnO₂ has been found to act as a catalyst for H₂O₂, which produces oxygen (O₂) and releases manganese ions (Mn²⁺), making it a H₂O₂-responsive T₁ contrast agent. Furthermore, generated O₂ can rejuvenate the oxygen supply to the tumor, which enhances its hypoxic environment, a crucial factor in inhibiting tumor growth and metastasis. The conversion of deoxyhemoglobin (Hb) to oxygenated hemoglobin (HbO₂) occurs due to generated O₂.^89–92 Hb is superparamagnetic and HbO₂ is diamagnetic. The transformation from Hb to HbO₂ leads to the reduction of the transverse relaxation rate (r₂) contributing to the high signal intensity of the tumor tissues present in T₂-weighted images.^93,94 Thus, MnO₂ proves to be an efficient oxygen producer and serves as a viable dual T₁–T₂ contrast agent for MRI.

Based on the mechanism, MnO₂ has been extensively studied as a T₁–T₂ dual contrast agent. For instance, Peng et al.⁹⁵ synthesized hybrid nanoparticles of Prussian blue (PB) and MnO₂ (PBMn) for imaging purposes using T₁–T₂-PAI. The presence of MnO₂ in PBMn led to a reduction in both the r₂ of PB and the signal intensity of artifacts inherent in T₂-weighted MR images. Additionally, PB in PBMn improved the H₂O₂ oxygen generation effect and oxygenated deoxygenated Hb to HbO₂. HbO₂ is diamagnetic and enhances the T₂-weighted signal intensity. The experimental results established that PBMn nanomaterials could serve as T₂-weighted magnetic contrast agents. Furthermore, the MnO₂ nanomaterials served as traditional T₁ MR and fluorescence imaging contrast agents, allowing them to be used as three-modality contrast agents for clinical disease diagnosis (Fig. 4b).

Here, more researchers are exploring the use of MnO₂ as a T₁–T₂ dual contrast agent. The discovery of a novel bidirectional magnetic resonance tuned nanoprobe that features bidirectional magnetic resonance tuned with dual-activated T₁ and T₂ magnetic resonance signals coupled with dual contrast enhances subtraction imaging.⁹⁶ When injected into patient-derived xenograft models, the nanoprobe demonstrated a high sensitivity in detecting microscopic intracranial brain tumors, while simultaneously displaying a significant increase in contrast enhancements with minimal background signals. Moreover, it can also be employed for the quantitative imaging of molecular targets in tumors. In another example, Zhao et al.⁹⁷ proposed the construction of yolk–shell nanohybrids (Fe₃O₄@C/MnO₂-PGEA) through a simple process. Making use of the unique yolk–shell structure, the nanohybrids offer accurate T₁–T₂ dual-mode magnetic resonance imaging by adequately exposing both the Fe₃O₄ core and MnO₂ shell.

Most importantly, Mn(II) released from nanoparticles of MnO₂ is easily metabolized by the kidneys. The biological mechanism lies in the semipermeable properties of the glomerular capillary wall, which consists of endothelial cells, the basement membrane and epithelial cells of the renal proximal tubules. The pore size of endothelial cells is approximately 100 nm, and that of the basement membrane is about 3 nm. The filter hole of the podocyte is around 32 nm. All solutions and molecules with a molecular weight lower than that of serum protein (68 kDa) and a hydrodynamic diameter smaller than 5–7 nm can cross the barrier. However, some small nanoparticles are retained and accumulate at the basement membrane to achieve MRI.⁹⁸ In contrast, MnO₂ nanoparticles are generally less than 10 nm in diameter.⁹⁹ Therefore, their basic properties determine their capabilities in T₁, T₂ and T₁–T₂ dual-modal magnetic resonance imaging. They can be cleared by the kidneys quickly and have a fast circulation time in the body, reducing the risk of toxic side effects and ensuring biological safety (Fig. 4c). In conclusion, MnO₂ nanoparticles have good biocompatibility and can serve as a strong foundation for subsequent applications as contrast agents.

3.2 The applications of MnO₂ nanomaterials in disease diagnosis

According to the imaging mechanism described above, MnO₂ nanoparticles play a key role in MRI disease diagnosis. Different disease states produce significantly different intra-cellular environments, including oxidative mediators with high concentrations of H₂O₂ in mitochondria and reducing mediators with increased glutathione or cysteine concentrations in the endosomes and cytoplasm.⁷⁰ This results in differences in various cytoplasmic metabolites and biomolecules. Based on these differences in disease states, manganese dioxide nanoparticles which are highly sensitive to weakly acidic and reducing mediators, can decompose and release Mn(II).⁷⁵ As a result, the MRI signal of Mn(II) in the diseased state differs from the signal in the surrounding normal state, enabling disease diagnosis.

3.2.1 Antimicrobial detection and inflammation imaging. Enzymatic processes play crucial roles in inflammatory responses. The reactants and biomarker molecules involved in these processes have significant potential for imaging. Inflammation can cause an upregulation of specific enzymes that could potentially serve as imaging targets. However, the concentrations of most enzymes are too low to be directly detected by MR probes.⁷⁰ Nevertheless, Mn-based MR probes have been designed to detect pathogens by producing detectable changes in signal.¹⁰⁰ These probes can chemically react with enzymes and be retained at active enzyme sites in the tissue, allowing for high-precision imaging of inflammatory sites.

Bacterial biofilms present a microenvironment of bacterial infections with characteristics such as weak acidity, hypoxia and overproduction that are distinct from those of healthy tissues.^101–103 MnO₂ nanoparticles can decompose in an acidic environment to form water-soluble Mn(II), making them useful for detecting bacterial microenvironments. Xiu et al.¹⁰⁴ designed a MnO₂-based nanoparticle platform that responded to microenvironments for MRI of biofilms. After intravenous or local injection, the T₁-weighted magnetic resonance signals of the biofilm-infected tissues were remarkably enhanced compared with those of healthy tissues.¹⁰⁵ This finding was further supported by quantitative analysis, demonstrating the excellent bacteria detection abilities of MnO₂ nanoparticles.

MnO₂ can be used to detect specific enzymes to enable targeted imaging of changes in the bacterial microenvironment. Myeloperoxidase (MPO) is an extracellular marker of inflammation that is a heme-containing enzyme produced by immune cells, such as neutrophils and macrophages. MPO is widely expressed in tissues as part of the inflammatory response and can be used for disease staging in some cases.¹⁰⁶ Furthermore, MnO₂ can enrich specifically in inflamed areas with weak acidity and hypoxia, allowing imaging of inflammation via detection of MPO. Qiu et al.¹⁰⁷ encapsulated budesonide in hollow mesoporous MnO₂ nanoparticles and dextran sulfate sodium (Fig. 5a). The nanoparticles could release anti-inflammatory medication, remove reactive oxygen species (ROS) and target active macrophages to reduce MPO levels. This method could be used for the diagnosis and treatment of inflammatory enteritis.

Fig. 5 (a) MnO₂ nanomaterials are used in the diagnosis and treatment of inflammatory enteritis.¹⁰⁷ Copyright 2022, Royal Society of Chemistry. (b) BMUIG preparation and (c) BMUIG uses in biomodal imaging and in combination with photobiologic therapy for osteomyelitis. (d) Pre- and post-BMIG injection T₁-weighted MR images of post-traumatic osteomyelitis mice, with red arrows indicating infected areas.¹⁰⁸ Copyright 2019, Elsevier.

Meanwhile, the study found that MnO₂ could be utilized for diagnosing and treating osteomyelitis. Lu et al.¹⁰⁸ synthesized a bacterial inflammation-specific multifunctional preparation known as bovine serum albumin (BSA)-MnO₂-ubiquitin-indocyanine green-gentamicin (BMUIG). This preparation was combined with high-resolution bimodal imaging and antibiotic and photodynamic therapy for osteomyelitis treatment (Fig. 5b and c). To evaluate the imaging effect of BMUIG, they intravenously injected BMUIG into a mouse model of acute osteomyelitis and used photoacoustic imaging and MRI (Fig. 5d). The results showed that BMUIG could quickly and precisely detect the infected area, presenting a new technique for osteomyelitis diagnosis. In conclusion, MnO₂ shows great potential for detecting antimicrobial activity and inflammation and awaits further research by future researchers.

3.2.2 Neurodegenerative disease imaging. Manganese-based contrast agents show great potential for neurodegenerative disease imaging. In contrast to Gd(III) contrast agents, Mn(II) can enter active neurons through voltage-gated Ca(II) channels, enabling the mapping of neuronal activity and projection tracing.⁷⁰ Despite Mn(II) entry via the decisive metal transporter (DMT), it does not affect the generation of Mn(II)-based signals in the brain. Mn(II) enhances MR contrasts at low doses, permitting longitudinal imaging of the same individual over short or long scan intervals.⁷³ Further, Mn(II) is a micronutrient that participates in several biological processes, and it has good biological safety. In conclusion, MnO₂ nanomaterials offer unique advantages for addressing neurodegenerative diseases.

Manganese-enhanced MRI (MEMRI) has the potential for preclinical research of the brain physiology in awake behaving animals. MRI can monitor behavior during Mn(II) take up and capture the high-intensity signal retrospectively, which provides a basis for detecting neuronal diseases. Mn(II) has unique physiological properties that make it an appealing nerve contrast agent, including the ability to monitor cell transport kinetics and neuronal projection anatomy in the brain,¹⁰⁹ progress of Alzheimer's disease,^110–112 emotion management,¹¹³ Parkinson's disease,¹¹⁴etc. Remarkably, MnO₂ can be reduced to Mn(II) in vivo, which plays a crucial role in imaging neurodegenerative diseases. Lopes et al.¹¹⁵ embedded a combination of hyaluronic acid (HA) and acrylic gellant (GG-MA) into MnO₂ nanoparticles. The results indicate that the nanoparticles have MEMRI properties and can be used for intrathecal injection, promoting localized healing of spinal cord tissues during neurodegenerative diseases.

In addition, some studies have confirmed the use of manganese dioxide for treating Alzheimer's disease. E. Park et al.¹¹⁶ utilized multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve imaging and therapeutic benefits in a well-characterized mouse model of Alzheimer's disease (Fig. 6a). Brain-penetrating MnO₂ nanoparticles successfully decreased hypoxia, neuroinflammation and oxidative stress. In addition, MnO₂ nanoparticles reduced amyloid protein in the cerebral cortex. MnO₂ nanoparticles could have positive impacts by enhancing microvascular integrity, cerebral blood flow and cerebral lymphatic clearance of amyloids. Collectively, these changes modify the brain microenvironment to create favorable conditions for sustained neural function.

Fig. 6 (a) FAIR-FISP magnetic resonance imaging was used to image blood flow in the cerebral cortex and subcortex in the brains of mice with advanced AD.¹¹⁶ Copyright 2023, Wiley-VCH. (b) Schematic of BM NPs for in vivo MR imaging of BBB permeability and for forecasting the transition of bleeding in the MCAO rat model.¹²² Copyright 2021, Royal Society of Chemistry. (c) Scheme of the preparation process for Ma@(MnO₂ + FTY) nanoparticles. (d) An illustration of Ma@(MnO₂ + FTY) therapy for the treatment of ischemic penumbra.¹²⁷ Copyright 2021, Wiley-VCH.

3.2.3 Acute ischemic stroke imaging. Furthermore, MnO₂ can effectively cross the blood–brain barrier (BBB) and be used to evaluate the prognostic impact of acute ischemic stroke treatment. Acute ischemic stroke, occurring when a blood clot abruptly occludes a cerebral blood artery, is a leading global contributor to disability and mortality.¹¹⁷ MRI is a traditional clinical tool in acute ischemic stroke diagnosis, being of paramount importance for ultra-early diagnosis and treatment evaluation.¹¹⁸ The primary objective of acute ischemic stroke therapy is to achieve reperfusion and save compromised neurons in the ischemic penumbra. However, reperfusion usually damages the blood–brain barrier, resulting in an often fatal complication, hemorrhagic transformation (HT).¹¹⁹ Predicting HT outcome in stroke patients now involves quantitative imaging of BBB permeability.^120,121 Hou et al.¹²² employed BSA MnO₂ nanoparticles (BM NPs) for imaging BBB permeability in stroke. BM NPs display a high T₁ relaxation ability (r₁ = 5.9 mM⁻¹ s⁻¹), exceptional MR contrast enhancement capability and notable biocompatibility. Thus, these NPs can non-invasively and promptly display BBB permeability in middle cerebral artery occlusion (MCAO) rats and effectively predict HT occurrence in MCAO rats (Fig. 6b). These studies are pivotal for enhancing the basic understanding of various nervous system pathologies and the advancement of clinical treatments for stroke patients.

Thrombolytic drugs administered in the treatment of ischemic strokes can lead to reperfusion injury, significantly hampering neurological function restoration. Furthermore, the process of reoxygenation after hypoxia can cause oxidative stress leading to immune cell activation, which causes a response that can damage normal brain tissue.¹²³ Moreover, immune cells activated in response cause damage to normal tissue in the brain. Thus, accurate assessment of reperfusion injury is critical to determining the cure rate of ischemic stroke patients.

Moreover, researchers aim to attain reperfusion in the ischemic penumbra in order to salvage damaged neurons, which is the principal purpose of most interventions in acute ischemic stroke therapy.¹²⁴ However, the main obstacle to neuronal survival is reperfusion injury in acute ischemic stroke.^125,126 Li et al.¹²⁷ employed macrophage-camouflaged honeycomb MnO₂ nanospheres loaded with fingolimod (FTY) to rescue the ischemic penumbra. The MnO₂ nanospheres facilitate the accumulation of cell adhesion molecules that are over-expressed on the damaged vascular endothelial cells at the site of brain damage through recognition mediated by macrophage membrane proteins, thereby enabling T₁ MRI (Fig. 6c and d). Additionally, the MnO₂ nanospheres possess the ability to consume excess H₂O₂ and transform it into dehydrogenated O₂. It can be decomposed and released in acidic lysosomes, thereby reducing oxidative stress, increasing the survival of injured neurons and reversing the proinflammatory microenvironment.

3.2.4 Tumor imaging. Malignant tumors, which originate from human epithelial tissues, pose an increasing threat to human health.¹²⁸ In 2020 alone, about 19.3 million people worldwide were diagnosed with such tumors, and a staggering 10 million lost their lives to these malignancies, according to the World Health Organization. Notably, mortality rates associated with these tumors are on the rise due to several factors, including the social environment, poor living habits and work-related stress. This ailment now ranks second globally in terms of common causes of death, in large part because symptoms lack clarity in the early stages, resulting in the majority of patients already finding themselves grappling with advanced stages of the disease when they are diagnosed. By this point, the cancer cells have already infiltrated various parts of their bodies, making it challenging to treat them with complete effectiveness through chemotherapy and surgery.¹²⁹ It has proved impossible thus far to diagnose early-stage tumors with a single diagnostic imaging technique in clinical practice. As researchers seek to address this issue, various drugs with applications in early tumor imaging have emerged as subjects of investigation.

In recent years, there have been several studies regarding the use of MnO₂ nanomaterials for tumor imaging via MRI. Due to their rapid growth and abundant blood supply, tumor cells exhibit wider gaps around the blood vessel walls than other cells, allowing the MnO₂ nanomaterials to enter cancerous cells through such openings. The MnO₂ nanomaterials are introduced into the blood, and using the abnormal tumor vascular gap, they leak into and accumulate in the cancerous tissue. As a result, there is a significant increase in MRI signals in the tumor area, but no significant signal enhancement in important organs, muscles and tissues with normal vascular gaps.¹³⁰

It is well-established that the tumor microenvironment (TME) is acidic, and MnO₂ can be reduced to Mn²⁺ in this acidic environment, enabling MRI enhancement at the tumor site. For instance, Gao et al.¹³¹ produced nanoprobes by coating MnO₂ on the black P25 titanium dioxide (b-P25) surface (b-P25@MnO₂) (Fig. 7a and b). These nanoprobes exhibit GSH-responsive MRI activity. In the TME, excess GSH reacts with MnO₂ to produce Mn²⁺, resulting in a longitudinal relaxation rate of up to 30.44 mM⁻¹ s⁻¹ for b-P25@MnO₂. This led to good intratumoral and cellular MRI findings. Similarly, Huang et al.¹³² employed oxidizable MnO₂ nanosheets to create nanoparticles for dual-activated MRI/fluorescence bimodal tumor imaging. The oxidizable MnO₂ nanosheets served as intracellular GSH-activated MRI contrast agents and DNA nanocarriers for imaging and targeted transport.

Fig. 7 (a) Schematic diagram of the b-P25@MnO₂ synthesis process and its GSH response and application in (b) MR imaging and improved PTT.¹³¹ Copyright 2021, Royal Society of Chemistry. (c) Schematic illustration of the development of a tumor-targeting MRI contrast agent based on melanin nanoparticles that chelate Mn²⁺ and have extremely high efficiency clearance in vivo.¹³³ Copyright 2021, Royal Society of Chemistry.

Also, MnO₂ has high biosafety as a MRI contrast agent. Xu et al.¹³³ proposed an innovative Mn²⁺-chelated ultrafine water-soluble melanin nanoparticle-based tumor-targeted MRI contrast agent (MNP-PEG-Mn) (Fig. 7c). MRI experiments in vivo demonstrated a high tumor targeting specificity after an intravenous injection of MNP-PEG-Mn into tumor bearing mice. Furthermore, MNP-PEG-Mn is associated with little toxicity to the body's tissues since it can be eliminated via hepatobiliary and renal pathways.

MnO₂ is capable of carrying various materials, including chemotherapeutic agents, photosensitizers and other therapeutic components, making it useful for MRI and optical imaging, as well as for loading purposes.¹³⁴ In the current study, amorphous MnO₂ was coated with polydopamine (PDA) and polyethylene glycol (PEG) to generate polydopamine@MnO₂-PEG (PDA@MnO₂-PEG) core–shell nanoparticles. These particles had uniform morphology and size and were employed for MRI-guided tumor photothermal therapy, taking advantage of their acid-sensitive properties. The study findings reveal that amorphous MnO₂ shells are acid-sensitive and effective T₁-weighted MRI agents. In the tumor models of mice, the MRI signals showed significant enhancements following injection compared to pre-injection measurements. In addition, PDA@MnO₂-PEG was used to perform effective photothermal treatment of tumors, as shown in in vivo experiments.¹³⁴ Furthermore, Laurie J. Rich et al.¹³⁵ used nano-crystalline NaYF₄:Nd³⁺/NaGdF₄ coated with MnO₂ to improve hyperthermia in head and neck squamous cell carcinoma (HNSCC) tumors (Fig. 8a). Mn²⁺ release in vasculature was observed through T₁-weighted MRI and photoacoustic imaging. The nanoparticles accumulated locally and systematically within tumors, significantly improving oxygenation in the tumor microenvironment in patient derived HNSCC xenograft models (Fig. 8b).

Fig. 8 (a) Synthesis of nano-sized NaYF₄:Nd³⁺/NaGdF₄ nanocrystals coated with nano-sized MnO₂. (b) Photoacoustic and MR imaging was performed to assess the imaging properties and the ability of usNP-MnO₂ to modulate hypoxia in vitro.¹³⁵ Copyright 2020, MDPI.

Recently published research has proved the potential of MnO₂ nanoparticles for the early detection of triple-negative breast cancer (TNBC). TNBC lacks the expression of human epidermal growth factor receptor 2, progesterone and estrogen receptors, which leads to a higher mortality rate than other types of breast cancer.^136–138 Chemotherapy often has a bad outcome for TNBC patients, resulting in a high tumor recurrence rate and the median survival is less than 12 months.^139,140 Therefore, early diagnosis and targeted therapy before tumor metastasis are essential for the effective treatment of TNBC patients.¹⁴¹ Hence, Peng et al.⁹⁵ synthesized biodegradable PB/MnO₂ hybrid nanocellulites for MRI and image-guided photodynamic therapy of breast cancers. Liang et al.¹⁴² developed core–shell gold nanocage MnO₂ (AM) nanoparticles using the template method. AM nanoparticles indicated excellent breast cancer MRI ability, which made the breast cancer targeting and in situ oxygenation monitoring of AM nanoparticles more accurate (Fig. 9a).

Fig. 9 (a) Preparation of core–shell AM nanoparticles and Mn²⁺ release due to acid/H₂O₂ response for TNBC enhanced MRI.¹⁴² Copyright 2018, Elsevier. (b) In vivo MRI T₁WI of the intracranial glioma after the intravenous injection of HA-PAH-MnO₂ NPs and HA-MnO₂ NPs at different time points.¹⁴⁶ Copyright 2019, Wiley. (c) Schematic diagram of GSH-responsive MnO₂ for NSCLC MRI and enhanced radiotherapy.¹⁴⁹ Copyright 2017 Cho, Choi, Kim, Goh and Choi. (d) MR imaging of acute myocardium infarction in rabbits contrasted by MnO₂@BSA nanocomposites.¹⁵⁷ Copyright 2020, Elsevier.

MnO₂ nanomaterials offer the significant likelihood for early detection of gliomas through MRI. A glioma, a primary central nervous system tumor caused by astrocytes,¹⁴³ is considered to be an extremely aggressive and common brain tumor.¹⁴⁴ Its rapid proliferation is due to the release of glutamate, causing excitotoxic cell death around the core and quick tumor invasion. Due to its high propensity for medication resistance and metastasis, the glioma is among the most fatal and threatening malignancies.¹⁴⁵ Fu et al.¹⁴⁶ synthesized multifunctional hyaluronic acid–MnO₂ nanoparticles (HA-MnO₂ NPs) by mixing sodium permanganate with aqueous hyaluronic acid (Fig. 9b). In the MRI detection of intracranial gliomas in rats, HA-MnO₂ NPs provided high imaging sensitivity with a duration of up to 3 days after intravenous injection. The study demonstrated that using HA-MnO₂ NPs reduced tumor hypoxia and was effective at detecting gliomas through MRI. Furthermore, Zhang et al.¹⁴⁷ developed MnO₂@BSA nanoparticles (NPs) for glioma imaging in the brain, producing high MR signals under acidic conditions in the tumor microenvironment due to the release of Mn²⁺. As a result, MnO₂@BSA NPs serve as favorable contrast agents for brain glioma imaging. In addition, Jiang et al.¹⁴⁸ developed tLyP-1 modified dopamine-β-cyclodextrin nanoparticles, which encapsulated paclitaxel and MnO₂, to improve the efficiency of chemotherapy and image contrast enhancement in gliomas. The nanoparticles accumulated at the tumor sites and crossed the BBB. The nanomaterials disintegrated under weak acidity and high H₂O₂ concentrations, causing the system to collapse, leading to the generation of Mn²⁺ and O₂. At the same time, these nanoparticles can be used to monitor tumor size through MRI in real time, providing a reliable basis for treatment.

MnO₂ was unexpectedly found to be specific for lung tumors in addition to imaging well-known tumors. Although MRI is unavailable for lung cancer due to the absence of protons, MnO₂ nanomaterials have exceptional advantages as lung magnetic resonance contrast agents. MnO₂ nanoparticles (MnO₂ NPs) synthesized by Mi Hyeon Cho et al.¹⁴⁹ using biocompatible polymers (polyvinylpyrrolidone and polyacrylic acid) demonstrated GSH responsive lysis and signal enhancement in MRI with or without gefitinib resistance in vitro for non-small cell lung cancer (Fig. 9c). MnO₂ NPs showed cytotoxic effects on cells and additional dose-dependent therapeutic effects when exposed to X-ray irradiation, opening up possibilities for the diagnosis and treatment of NSCLC. In the study, Cao et al.¹⁵⁰ proposed the combination of MnO₂ with the photosensitizer chlorin e6 (Ce6) and mesenchymal stem cells (MSCs) (MnO₂@Ce6-MSCs) as a potential nanoparticle for the diagnosis and treatment of lung cancer, reducing mortality rates. Therefore, MnO₂ proves to be highly promising in the field of tumor imaging, providing a basis for the subsequent integration of diagnosis and treatment.

3.2.5 Myocardial infarction imaging. In addition to its use in tumor imaging, MnO₂ can also be utilized in the diagnosis of myocardial infarction (MI) which is the leading cause of death globally. Despite drug therapy, patients with MI continue to have high morbidity and mortality rates due to irreversible myocardial remodeling at present.¹⁵¹ Notably, inadequate myocardial blood supply causes acute myocardial infarction (AMI), which poses a significant challenge to public health. Early and precise detection of MI, particularly AMI, is necessary for improving the quality and efficiency of care. Gd-chelated contrast agents have been employed in MRI scans of MI to provide higher contrast enhancements at the infarcted sites approximately 10 to 15 minutes after administration since they clear more slowly from the infarcted area than from the normal myocardium.^152,153 Nevertheless, Gd-chelated contrast agents cannot distinguish between MI sites and edema areas,¹⁵⁴ and require high dose injections, increasing the risk of nephrogenic fibrosis.^155,156 Thus, new contrast agents for the diagnosis of AMI are called for. Wang et al.¹⁵⁷ designed a low pH-sensitive albumin nanocomposite with MnO₂ (MnO₂@BSA) for T₁-weighted MRI of myocardial infarction (Fig. 9d). The MnO₂@BSA nanocomposites can accumulate progressively in the areas of AMI and be taken up by inflammatory macrophages due to the low pH microenvironment. The released Mn²⁺ ions can interact with ambient albumin, leading to enhanced imaging contrasts. Importantly, MnO₂@BSA shows rapid evacuation kinetics after systemic injection and exhibits superior performance in MRI contrast enhancement in rabbit models with AMI, demonstrating its potential as a promising diagnostic agent for the early detection of AMI.

After conducting research on MnO₂ nanomaterials for disease imaging, it is evident that there has been a surge in research interest to develop MnO₂ nanomaterials with improved properties, such as subtle design, high imaging efficiency, good biosafety and clinical efficiency. This has resulted in a plethora of new MnO₂ nanomaterials being reported, offering an array of promising approaches for the clinical application of manganese-based contrast agents in disease diagnosis and treatment. We anticipate that these recent advancements will accelerate the translation of manganese-based contrast agents for clinical disease imaging in the future.

4. MnO₂ for fluorescence imaging

Fluorescence is a phenomenon resulting from excitation with light, during which a fluorophore reaches a high-energy state and then releases energy as emission light.¹⁵⁸ Therefore, fluorescence imaging takes advantage of the luminescence properties of fluorescence to image biological tissues. In comparison with traditional imaging methods, fluorescence imaging is characterized by high sensitivity, simultaneous imaging of multiple groups of samples, stability and biological safety.¹⁵⁹ By selecting specific fluorescent proteins or dyes, fluorescence imaging is helpful for research and diagnosis of diseases in clinical practice.¹³⁷

GSH is the most prevalent non-protein thiol species in mammalian cells and is essential for defending against damage caused by toxins and free radicals.¹⁶⁰ It functions as an endogenous antioxidant and is present in a reduced state under normal conditions. Many diseases including Alzheimer's disease, osteoporosis, acquired immune deficiency syndrome and atherosclerosis have been linked to GSH levels.^161–164 Therefore, detecting glutathione levels is an essential method for clinical processing and diagnosis of relevant diseases. However, current fluorescent probes are often subject to the external environment, which reduces their sensitivity and photostability due to photobleaching and premature leakage.¹⁶⁵

Due to its light absorption ability, MnO₂ can rapidly and accurately activate various functions after reduction triggered by GSH, including quenching fluorescence, targeting specific aptamer carriers and activating an MRI imaging agent in the presence of intracellular GSH. Therefore, MnO₂ can be used for detecting glutathione.¹⁶⁶ A new nanoprobe was reported that coated negatively charged MnO₂ nanosheets with positively charged polyethylenimine (PEI) polymer and then coupled them to fluorescein isothiocyanate (FITC) using thiourea ligation (MnO₂-PEI-FITC) (Fig. 10a).¹⁶⁷ The MnO₂-PEI-FITC nanoprobes exhibited weak fluorescence, which was absorbed by FITC, but FITC fluorescence was excited in the presence of GSH. At the same time, MnO₂ was decomposed to Mn²⁺, enabling detection of low background levels in yeast cells and the inner epidermal tissue of onions. In addition, Yao et al.¹⁶⁸ developed a NIR activatable fluorescence nanoprobe for the imaging and determination of intracellular GSH based on a core–shell nanoparticle, consisting of NIR emitting gold nanocluster doped silica as the fluorescent core and manganese dioxide as the GSH-responsive shell (AuNCs@MnO₂). The MnO₂ shell preferentially absorbed the excitation light, thus leading to fluorescence quenching. Upon addition of GSH, the fluorescence of the nanoprobe was restored along with the reduction of MnO₂ to Mn²⁺, and could specifically detect GSH signals in cells. Similarly, Du et al.¹⁶⁹ also confirmed the potential of MnO₂ nanomaterials as glutathione detection agents.

Fig. 10 (a) The steps involved in creating the MnO₂-PEI-FITC nanoprobe and its response mechanism for detecting GSH.¹⁶⁷ Copyright 2021, Royal Society of Chemistry. (b) Schematic illustration of the preparation of AuNCs@MnO₂ core–shell nanoprobes and their application in the NIR fluorescence imaging of intracellular GSH.¹⁶⁸ Copyright 2021, Royal Society of Chemistry.

Simultaneously, MnO₂ can be paired with near-infrared fluorescent (NIR) nanomaterials to develop responsive fluorescent nanoprobes.¹⁷⁰ NIR fluorescent nanomaterials have exceptional properties, including good membrane permeability, photostability, deep tissue penetration and low autofluorescence.¹⁷¹ These nanomaterials can also avoid renal filtration and improve the signal-to-noise ratio, enabling long-term detection in live cells.¹⁷² For example, Song et al.¹⁷² illustrated a novel fluorescence nanoprobe constructed using graphene quantum dots (GQDs) as near-infrared emitters and MnO₂ as the fluorescence quencher (MnO₂–GQDs). The MnO₂–GQD nanoprobes were degraded in the presence of GSH, releasing Mn²⁺ and GQDs separately and causing the quenched fluorescence to be recovered. Similarly, MnO₂ was paired with the photosensitizer Ce6, which displayed good fluorescence imaging both in vivo and in vitro.¹⁷³ Furthermore, MnO₂ nanomaterials can enable dual-mode MRI and fluorescence imaging by reacting with GSH to produce Mn²⁺. A study reported a dual-mode MRI/fluorescence platform for tumor cell imaging that detected GSH.¹⁷⁴ Upon endocytosis, MnO₂ nanosheets and intracellular GSH can interact, resulting in the production of a large amount of Mn²⁺, which can be amplified by the circle amplification (RCA) reaction (Fig. 11a). Meanwhile, GSH treatment restores most of the fluorescence signal. MnO₂ grown in situ on the surface of oleic acid-coated UCNPs can enable multimodal MRI and fluorescence imaging.¹⁷⁵ This technique enables improved imaging sensitivity, tissue penetration and can guide subsequent clinical practice by detecting glutathione.

Fig. 11 (a) The MnO₂–GQD nanoprobe for the detection of GSH.¹⁷⁴ Copyright 2018, Elsevier. (b) Based on DNAzyme–MnO₂ nanoprobes, an experimental method for identifying and visualizing miRNA-155 in living cells has been developed.¹⁸¹ Copyright 2021, Royal Society of Chemistry.

MnO₂ nanomaterials with the ability to detect GSH can also be used for cancer cell-targeted imaging. MnO₂ can rapidly degrade in the presence of reductive agents such as an increase of glutathione in cancer cells.¹⁷⁶ Using host–guest interactions and self-assembly between fluorescent polymers and MnO₂ 2D materials, Wang et al.¹⁷⁷ developed a 2D probe for cancer cell-targeted fluorescence imaging in liver and TNBC cells based on biothiol responses.

Moreover, MnO₂ can be targeted to release fluorescent signals for accurately detecting microRNAs, which can be utilized as biomarkers for clinical diagnoses and play a crucial role in many biological processes.^178–180 For example, to introduce DNAzyme probes into cells through endocytosis, MnO₂ nanosheets were used as carriers and were reduced to Mn²⁺ by intracellular GSH, thereby releasing the probes (Fig. 11b).¹⁸¹ The produced Mn²⁺ activated the DNAzyme probes, causing fluorescence signal changes. These fluorescence imaging techniques effectively detected miRNA-155 in HeLa and HepG2 cells, this is useful for cancer detection and investigating biological events involving miRNAs. In summary, MnO₂ can interact with various substances, producing fluorescence to investigate biological process.

5. MnO₂ for photoacoustic imaging

Photoacoustic (PA) imaging is a recently developed non-invasive and non-ionizing biomedical imaging technique that has gained popularity in recent years. Pulsed laser irradiation of biological tissues causes the tissues’ optical absorption domain to produce ultrasonic signals. These signals carry characteristic information and can reconstruct an image of optical absorption in the tissues. PA imaging has gained significant attention due to its advantages of high optical resolution in both space and time.^182,183 Nevertheless, the diagnosis of diseases using PA imaging relies on the development of imaging contrast agents that are capable of converting the thermal energy produced by pulsed laser irradiation into ultrasound signals.^184–186 Consequently, a variety of materials such as semiconductors, noble metals and polymers have been utilized as PA imaging agents.¹⁸⁷ In their study, Yan and colleagues¹⁸ synthesized a polymer of gold nanorods (Au NRs) and manganese dioxide nanosheets (Au NR–MnO₂). Based on their findings, Au NR–MnO₂ exhibits a stronger absorption in the NIR region compared to Au NRs. Additionally, its PA intensity is 2.7 times greater than that of Au NRs when dispersed in water. Importantly, Au NR–MnO₂ was successfully employed for in vivo tumor imaging. Therefore, Au NR–MnO₂ polymers offer an effective strategy for improving PA imaging (Fig. 12a and b).

Fig. 12 (a) A glutathione (GSH)-triggered gold@manganese dioxide (Au@MnO₂) smart theranostic agent for photoacoustic and MR dual-imaging-guided photothermal-enhanced chemodynamic therapy.¹⁸ Copyright 2021, Elsevier. (b) PA imaging of different materials (MnO₂, Au NRs, Au NR–MnO₂). (c) PA imaging of Au NR–MnO₂ at different concentrations.¹⁹⁵ Copyright 2021, Royal Society of Chemistry.

Gold–manganese dioxide nanoparticles have shown potential for improving the effectiveness of cancer diagnosis and treatment through multimodal imaging.^188–190 One study shows the result of the combination of photoacoustic and MRI imaging for more accurate diagnosis.^191–194 Wang et al.¹⁹⁵ demonstrated that gold–manganese dioxide core–shell nanostructures could be used for dual photoacoustic and MR imaging, showing high stability under physiological conditions (Fig. 12c). When accumulated at the tumor site, Au@MnO₂ induced a series of reactions whereby MnO₂ was converted into Mn²⁺ due to high levels of GSH present, which enhanced the contrast of photoacoustic imaging and MRI.

Combining different functional materials with MnO₂ can enable multimodal imaging effects. Various approaches have been developed to generate MnO₂/PB nanostructures for dual-mode MRI/PA imaging.^95,196,197 For example, Xu et al.¹⁹⁸ described a novel imaging nanomaterial composed of MnO₂-coated porous Pt@CeO₂ core–shell nanostructures (Pt@CeO₂@MnO₂). The porous Pt core gave the core–shell nanostructure a high photothermal conversion efficiency in the NIR, which led to good PA imaging effect for tumor imaging. Additionally, photoacoustic imaging is frequently combined with therapy and exhibits significant potential for therapeutic integration.

6. Treatment

To date, MnO₂ nanomaterials have been applied in various biomedical domains. In particular, MnO₂ nanomaterials exhibit significant potential regarding cancer treatment owing to their unique nanostructures and physicochemical characteristics.¹⁹⁹ The primary application of MnO₂ nanomaterials consists of various anti-cancer therapies, including photodynamic therapy (PDT), radiation therapy (RIT), photothermal therapy (PTT) and chemodynamic therapy (CDT).

Photodynamic therapy (PDT) is a therapeutic technique that employs photosensitizing agents and laser activation (Fig. 13a).^200–202 Photosensitizers absorb light at specific wavelengths and activate oxygen to produce cytotoxic reactive oxygen species (ROS), which can destroy tumor tissues.^203–206 However, the uncontrolled proliferation of tumor cells, in combination with PDT, results in oxygen deprivation due to oxygen consumption, reducing the efficiency of PDT while generating harmful metabolites (e.g., H₂O₂) during hypoxia.²⁰⁷ Nanoscale MnO₂ can mitigate tumor hypoxia by interacting with harmful substances such as H⁺, H₂O₂, etc., thus enhancing the therapeutic effects of PDT, while concurrently transforming into Mn²⁺ to amplify MRI contrast.^208–211 Additionally, MnO₂ nanostructures, characterized by a large surface area and inner cavity, can accommodate photosensitizers effectively, facilitating fluorescence imaging.

Fig. 13 (a) Schematic diagram of the PDT effect. (b) Schematic of the effects of other treatments.

Numerous MnO₂ nanomaterials are loaded with photosensitizers for disease therapy. Sun et al.²¹² designed and constructed a delivery system of a hydrophobic photosensitizer (BSA-MnO₂/Ce6@ZIF-8) based on a metal–organic framework for MRI-guided PDT. With BSA-MnO₂ modification of the Ce6@ZIF-8 surface, BSA-MnO₂/Ce6@ZIF-8 can generate oxygen in the TME, consequently enhancing the photodynamic activity of cancer treatment. Yang et al.¹⁷³ assembled glucose oxidase (GOx)-coated mesoporous silica nanoparticles (MONs), MnO₂ nanosheets and the photosensitizer Ce6, producing a smart nanoprobe (MONsGOx@MnO₂-Ce6), thus greatly improving the efficacy of starvation and photodynamic cancer combination therapy. Ji et al.²¹³ designed a novel multifunctional nanosystem, CaO₂/MnO₂@polydopamine-methylene blue (MB) nanosheet (CMP-MB), which had the same PDT and MRI effects. Additionally, Liu et al.²¹⁴ proposed a new idea for the combination of inorganic nanomaterials with MnO₂, confirming its role in PDT.

Radiation therapy (RIT) is a prevalent method for the eradication of tumors (Fig. 13b).²¹⁵ Ionizing radiation is responsible for the eradication of cancerous cells in radio-therapy. However, the primary impediment to radiotherapy is the hypoxic environment within tumors. MnO₂ can promptly modify the hypoxic microenvironment by breaking down H₂O₂ into oxygen, augmenting RIT efficiency greatly. Therefore, MnO₂ nanomaterials can be utilized as a radiosensitizer to improve the efficiency of radiotherapy.²¹⁶ Recently, Tian et al.²¹⁷ created a novel nanoplatform for RIT via the combination of ¹³¹I-labeled HSA with MnO₂ (¹³¹I-HSA-MnO₂). MnO₂ can induce the degradation of endogenous H₂O₂, leading to the production of oxygen that mitigates tumor hypoxia-related RIT resistance. The experiments demonstrated that the nanoparticles could be employed as effective RIT agents for anti-cancer treatment.

Photothermal therapy (PTT) is another promising method for tumor killing (Fig. 13b).^218–220 Under the influence of radiation, photothermal nanoparticles convert light into heat. To enhance the efficacy of photothermal nanoparticles in tumor ablation, Liu et al.²²¹ developed a highly sensitive 2D-MnO₂ nanosheet for PTT. As anticipated, the MnO₂ nanosheet exhibited a high photothermal conversion rate, ensuring more efficient and effective tumor ablation.

Chemodynamic therapy (CDT) is a new therapeutic strategy that generates hydroxyl radicals (˙OH) to kill tumor cells in situ (Fig. 13b).²²² It does not require the application of external energy and can generate irreversible damage to tumor cells’ lipids, mitochondria, DNA and proteins. Thus, this approach avoids the side effects and tissue penetration depth restrictions.²²³ The presence of MnO₂ can deplete GSH and facilitate ˙OH production, enhancing CDT's effectiveness. Ding et al.²²⁴ synthesized a hybrid nanoplatform (UCMN) that coupled upconversion nanoparticles (UCNP) and MnO₂. Its complex structure promotes ˙OH production through GSH depletion and cisplatin activation, significantly improving the efficiency of CDT. Additionally, the reaction of MnO₂ with GSH to produce Mn²⁺ facilitates MR image contrast.

In recent years, an increasing number of researchers have investigated the combination of multiple treatment modes. Multiple treatment modes offer advantages over single treatment modes, thus improving the effectiveness of cancer treatment. PDT is effective at treating tumors, but its applicability is constrained by the tumor microenvironment with diverse properties and low tumor permeability of the materials.²²⁵ In the context of PTT, the upregulation of heat-shock proteins affects the efficacy of this treatment. A previous study demonstrated that PDT-produced ROS were capable of inhibiting the production of heat shock proteins, which, in turn, enhanced the photothermal effects.^226,227 Furthermore, the increase in temperature caused by the photothermal effect itself is also likely to improve PDT efficacy.²¹⁴ Therefore, the combination of PDT and PTT is expected to produce a synergistic therapeutic effect. To this end, Sun et al.²²⁸ developed a multifunctional therapeutic platform (MnO₂–SiO₂–APTES&Ce6 (MSA&C)) based on MnO₂ nanoflowers, which synergistically augmented PDT and PTT, demonstrating promising therapeutic effects. Similarly, Li et al.²²⁹ successfully developed excellent nanotherapeutic Bi₂S₃–MnO₂@BSA-Ce6 (BMBC) NPs, which displayed promising in vitro synergistic effects of PTT and PDT in cell experiments. Additionally, studies by Zhang et al.²³⁰ and Xu et al.¹⁹⁸ simultaneously confirmed the advantages of MnO₂ nanomaterials as a combination of PTT and PDT.

MnO₂ nanomaterials exhibit a high specific surface area, potent adsorption capability and biocompatibility, making them amenable for loading various anticancer drugs into MnO₂ nanocarriers.²³¹ It is well-established that the degradation of MnO₂ in low-acidity and high-GSH environments coincides with drug release. Tang et al.²³² recently reported the successful design of a MnO₂ nanoparticle loaded with the in vitro anticancer drug Adriamycin and an aza-bodipy photosensitizer. The resultant nanocarriers were shown to respond well to the TME and exhibit degradability. The products were found to effectively aggregate at the tumor site and underwent time-dependent clearance mainly through the liver and kidneys. The exceptional performance of MnO₂ in recent years presents an opportunity to enhance chemotherapeutic precision.

7. Conclusions and perspectives

MnO₂ nanomaterials possess numerous superior properties that have garnered significant attention in the field of imaging. This review presents the comprehensive synthesis of MnO₂ nanomaterials and their biomedical applications, with an emphasis on recent applications of MnO₂ in MRI. MnO₂ nanomaterials exhibit paramagnetism and rapid exchange with hydrogen protons, resulting in enhanced T₁-weighted signals. Accordingly, MnO₂ nanomaterials have been utilized for inflammation imaging, brain imaging, tumor imaging and myocardial infarction imaging. MnO₂ nanomaterials are also straightforward to synthesize, eco-friendly, low-cost, highly biocompatible and possess excellent photothermal properties. Furthermore, they excel in therapeutic applications. MnO₂ also demonstrates great potential in fluorescence imaging and photoacoustic imaging, which together produce excellent results when combined with other therapeutic strategies, thereby providing robust support for subsequent clinical transformations. While numerous studies have demonstrated the excellent performance of MnO₂ nano-materials, several challenges remain.

(1) To facilitate the early diagnosis of diseases, imaging contrast agents must exhibit enhanced sensitivity and specificity. However, in the case of molecular changes caused by the disease, morphological structures remain predominantly unaltered, thereby making it challenging for MnO₂ nanomaterials to achieve precise molecular imaging. Consequently, the precise imaging of molecular changes necessitates the alteration of the shape and size of MnO₂ nanomaterials, thereby enhancing sensitivity and enabling the rapid assessment of benign and malignant properties.

(2) The clinical translation and application of MnO₂ are crucial aspects of its usefulness. MnO₂ nanomaterials possess outstanding properties, leading to various potential applications. However, most of the research findings remain in the domain of basic research and have not been successfully implemented in clinical practice. Hence, it is imperative that multifunctional nanomaterials based on MnO₂ are further developed, thereby facilitating their utilization in the clinical milieu.

(3) Despite several studies showing that MnO₂ nanomaterials possess an exceptional level of biosafety, the underlying biological toxicity, potential risks and metabolic processes have not been extensively studied. An in-depth understanding of biosafety is essential. Therefore, future studies should focus on exploring the long-term biosafety of MnO₂ nanomaterials and demonstrating their biocompatibility advantages as a novel type of magnetic resonance contrast agent.

(4) Several studies have established a significant correlation between manganese exposure and neurodegenerative diseases.²³³ Interestingly, the relationship between Mn over-exposure and Alzheimer's disease seems to be converse.^234,235 It is widely acknowledged that Mn neurotoxicity can significantly impact neurodevelopment of the brain. However, Mn ions can be modified by various strategies to reduce toxicity.

In this review, we introduced a variety of modification strategies, including assembly with proteins, the preparation of hydrogels or surface modification, etc. Experimental results showed that all showed good biocompatibility in vivo and in vitro, demonstrating the reduction of Mn ion toxicity. Therefore, we need to summarize the results and continue the research, so that MnO₂ contrast agents can be applied in clinical practice to solve real issues. In conclusion, the application of MnO₂ nanomaterials for medical diagnosis and treatment is a pressing concern. The increased utilization of these nanomaterials could aid with enhancing the cure rates of diseases such as cancer, contributing significantly to human health.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Sichuan Foundation for Distinguished Young Scholars (2022JDJQ0049); the Chengdu International Science and Technology Cooperation Fund (Grant 2019-GH02-00074-HZ); the Chengdu Science and Technology Bureau (Grant 2021-YF05-00698-SN); and the Scientific and Technological Achievements Transformation Fund of West China Hospital, Sichuan University (Grant CGZH21002).

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Footnote

† Both authors contributed equally.

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