MRI is a radiation-free imaging technique that offers greater penetration depth and high-resolution anatomical images. It has become a crucial clinical tool for early cancer diagnosis (Petralia et al., 2019). To achieve higher imaging contrast, the use of contrast agents is inevitable. Gd³⁺ complexes are commonly employed as contrast agents in MRI (Wahsner et al., 2019; Lu et al., 2022b). However, Gd³⁺ agents may accumulate in the kidneys and brain tissues post-metabolism, posing significant risks to the body (Kanda et al., 2015; Rudnick et al., 2021). This has prompted the search for safer contrast agents. Manganese-based agents were among the earliest reported enhancers for T1-weighted MRI (Niesman et al., 1990). With advancements in nanotechnology, TME responsive manganese nanomaterials have regained attention (Cai et al., 2019; Chen et al., 2022a; Deng et al., 2023). Progress in nanodelivery techniques has led to the emergence of various manganese-based nano-platforms with passive or active targeting capabilities (Patra et al., 2018; Mo et al., 2022). These platforms can respond to the acidic TME, release paramagnetic Mn²⁺, and achieve precise tumor imaging.

In 2020, Shi and co-workers synthesized MnCO₃ nanoparticles using a precipitation method. Further modification with polyethylene glycol (PEG) yielded MnCO₃ nanorhombuses (MnNRs) (Zhu et al., 2021). MnNRs served as ultra-sensitive T1-weighted MRI contrast agents, exhibiting significant T1 relaxation enhancement in weakly acidic TME conditions. In vivo mouse MRI experiments, these MnCO₃ nanoparticles selectively highlighted subcutaneous tumors from their periphery to their core. Compared to traditional gadolinium agents Primovist and MnO@PEG, this MnCO₃ nano-agent enabled high-contrast detection of millimeter-sized liver metastases (Figure 2) (Zhu et al., 2021) and efficient liver excretion through the gallbladder. In subsequent hematoxylin and eosin (H&E) staining and biochemical marker analyses, no evident microscopic lesions were observed. The key biochemical indicators exhibited similarity to the control group, indicating the favorable biocompatibility and low toxicity of MnNRs.

The pH-responsive manganese nanomaterials enable faster and higher tumor imaging sensitivity than clinically used Gd contrast agents. Furthermore, combining manganese nanomaterials with other magnetic metal nanomaterials can further enhance the contrast of MRI (Fan et al., 2021; Wang et al., 2022b; Carregal-Romero et al., 2022). For instance, in a study conducted in 2022, the Tian team developed manganese silicon iron SPIO@SiO₂@MnO₂ nanomaterials (Lu et al., 2022a). By comparing them with normal tissue, they observed that in the acidic environment of cancer or inflamed tissue, the MnO₂ layer decomposed into magnetic-active Mn²⁺ (T1-weighted). They used an imaging processing technique called “dual-contrast enhanced subtraction” to further integrate T1 and T2 contrast differences to enhance imaging sensitivity, enabling the detection of tiny liver metastases.

In addition to responding to the acidic TME, MnNMs can also enhance MRI by reacting with GSH. In 2019, the Hu research team developed hollow manganese/cobalt oxide nanoparticles (MCO NPs) (Ren et al., 2019). These MCO NPs, responsive to GSH, can degrade into Mn²⁺ and Co²⁺, thereby augmenting T1 and T2 weighted MRI contrast. Upon intravenous injection, histological staining images with H&E revealed no significant differences between phosphate buffer solution (PBS) and MCO NPs. This finding substantiates their relative safety.

In summary, carefully designed MnNMs can respond to the TME, decompose, and release Mn²⁺, effectively enhancing MRI signals and improving the efficiency of cancer diagnosis.

PAI is an imaging technology that combines optics and acoustics. It irradiates a target object with pulsed or modulated laser light. The target object absorbs light energy and converts it into heat energy. Target object then undergoes thermal expansion and contraction and radiates sound waves outward. By receiving Acoustic signal, ultrasound detector can achieve image reconstruction of the data (Attia et al., 2019).

PAI contrast agents are substances designed to enhance the contrast of photoacoustic imaging by absorbing light energy and inducing acoustic vibrations in tissues, thereby generating detectable photoacoustic signals. Various contrast agents have been developed for PAI with the aim of improving imaging contrast (Fu et al., 2019). Nanoparticles, including both plasmonic and non-plasmonic types ranging in size from nanometers to hundreds of nanometers, have been employed for this purpose.

In recent years, MnNMs have been widely studied in the field of PAI due to their responsiveness and excellent light absorption properties (Hu et al., 2019; Huang et al., 2019; Lv et al., 2022). In 2021, the Jiang research team fabricated MnO₂-coated porous Pt@CeO₂ core-shell nanostructures (Pt@CeO₂@MnO₂) (Xu et al., 2021a). The introduction of MnO₂ nanomaterials not only imparts responsiveness to the TME to the nanostructure but also enhances light absorption capability significantly. In comparison to Pt NPs and Pt@CeO₂ nanostructures, the Pt@CeO₂@MnO₂ nanostructure exhibits a substantial improvement in light absorption across the ultraviolet to NIR range. Importantly, 24 h post-injection of Pt@CeO₂@MnO₂, the photoacoustic intensity in the tumor region remains at 70% of the peak value (Figure 3) (Xu et al., 2021a). Prolonged tumor retention indicates the accumulation of MnO₂ nanomaterials in the tumor through the enhanced permeability and retention (EPR) effect.

Manganese nanomaterials accumulate at tumor sites through the response to the TME and the EPR effect. Due to their outstanding light absorption properties, manganese nanomaterials effectively enhance PAI signals. This positions manganese nanomaterials as promising substances for PAI contrast agents.

NIR-FL is an imaging technique that exploits light in the NIR region for the excitation and detection of fluorescence signals. By exciting fluorescence signals at the tumor site, effective NIR-FL of tumors can be achieved. Currently, this technology finds extensive applications in the field of tumor surgery (Li et al., 2021). The indispensable component for achieving NIR-FL of tumors is the use of fluorescent probes. Nanomaterials hold a crucial position in NIR-FL due to their optical properties, tunability of surface modifications, and biocompatibility (Jiang et al., 2023).

In NIR-FL, manganese fluorescent nanoprobes can respond to the TME and enhance the effectiveness of tumor imaging. Liu and co-workers developed a hollowed virus bionic MnO₂ nanoshell, internally loaded with IR1061 and anchored with quantum dots (PbS@CdS) on the surface (Wang et al., 2022c). Upon triggering the MnO₂ to respond to the TME leading to the degradation and subsequent release of IR1061, precise visualization of tumor margins is achieved. This approach serves the dual purpose of diagnosis and synergistic therapy.

By combining with indocyanine-green (ICG), MnNMs can even enhance the detection of sentinel lymph node metastases associated with tumors. In the study carried out by Ai and co-workers, Manganese porphyrin/ICG nanoparticles were synthesized under the influence of Pluronic F127 surfactant (Fu et al., 2022). Following the subcutaneous injection of this manganese nanomaterial into the footpad of mice, the changes in NIR FL signal intensity were monitored within 24 h. The fluorescence signal intensity variation in the right lymph node (tumor metastatic sentinel lymph node, T-SLN) exceeds that in the left lymph node (normal popliteal lymph node, N-LN). This facilitated a precise differentiation between normal lymph nodes and sentinel lymph nodes linked to tumor metastasis (Figure 4) (Fu et al., 2022).

In summary, MnNMs can be engineered as fluorescent nanoprobes responsive to the TME, facilitating the enhanced release of fluorescent agent and augmentation of NIR-FL. Varied imaging outcomes can be achieved by loading MnNMs with distinct fluorescent substances. These observations underscore the potential of MnNMs in NIR-FL, offering novel insights into cancer diagnostics.

Stimulus-responsive nanoprobes with integrated multimodal imaging capabilities are highly desirable and dependable for precise tumor visualization. Multimodal imaging methods offer complementary advantages and have gradually become a focus of early cancer screening (Lee et al., 2014). Manganese nanomaterial contrast agents emerge as crucial candidates for MRI contrast agents. Consequently, research on multimodal imaging based on MRI in the field of manganese nanomaterials is continually expanding (Jin et al., 2020; Wen et al., 2022).

The integration of PAI and MRI with the use of MnNMs has the potential to significantly enhance tumor diagnostic capabilities. Combining these two modalities enables the simultaneous acquisition of information at both the molecular and tissue structural levels within the same image. Huang and colleagues devised a method involving the plasma modulation of Gold Nanorods (GNRs) through MnO₂ coating to produce GNR@SiO₂@MnO₂ (GSM) (He et al., 2021). A dose of 5 mg kg⁻¹ of GSM was intravenously administered to mice bearing U87MG tumors, followed by MRI and PAI. The PAI signal from the tumor peaked 4 h after injection, whereas the strongest MRI signal was detected 8 h after injection, indicating a 4-h delay in the MRI signal compared to the PAI signal (Figure 5) (He et al., 2021). This delay could be attributed to the gradual degradation of MnO₂ in the acidic TME, leading to the release of Mn²⁺ and thereby enhancing the MRI contrast between normal tissue and the tumor.

The combination of MRI and PET is also one of the hot spots in cancer diagnosis research in recent years. Compared to PET-CT, PET-MRI offers advantages such as high image quality, fast scan speeds, and minimal X-ray radiation exposure (Spick et al., 2016). In 2018, a dual-modal imaging probe for PET-MRI was developed by Chen and colleagues (Zhu et al., 2018a). They constructed folic acid-modified multifunctional polyethyleneimine-coated Mn₃O₄ nanoparticles, which were subsequently labeled with the radioactive isotope ⁶⁴Cu. This probe demonstrated excellent in vivo targeted PET imaging for tumors overexpressing the folate receptor, accompanied by efficient T1-weighted MRI images. The MRI signal intensity enhances with an increase in the concentration of Mn₃O₄ nanoparticles.

The combination of MRI and NIR-FL is also widely recognized and studied. Wang and their team engineered a hollow mesoporous manganese-doped, DOX-loaded SiO₂ shell (Mn-ZGOCS-PEG) (Zou et al., 2021). Mn-ZGOCS-PEG generates Mn²⁺ in response to reductive and acidic TME, enhancing MRI and achieving clear differentiation between muscle and tumor tissues. Over time, as Mn-ZGOCS-PEG degrades within the tumor, the NIR-FL signal at the tumor site gradually strengthens, reaching stability at 60 min, with a sustained NIR-FL signal observed in the tumor area at 180 min.

Integrating multiple imaging modalities for comprehensive tumor visualization is a key goal in cancer treatment, aiming for higher precision and personalization. The paramagnetic properties and tumor-targeting specificity of MnNMs make them highly promising in the field of cancer multimodal imaging diagnosis.

PDT is a cancer treatment that utilizes visible light, near-infrared light, or ultraviolet light as an excitation source (Li et al., 2020). Under light exposure, tumor cells can undergo phototoxic cell death induced by light-sensitive materials generating toxic reactive oxygen species (ROS). Currently, a great number of research is focused on MnNMs due to their ability to improve the hypoxic TME and facilitate photosensitizer delivery in PDT (Xu et al., 2021c; Cheng et al., 2022).

In 2021, Zhang and colleagues devised an innovative strategy to tackle the issue of low levels of ROS in the TME (Figure 6) (Liu et al., 2021). They encapsulated small-sized Mn₃O₄-Ce6 nanoparticles (MC) within dendritic mesoporous SiO₂ nanoparticles and subsequently coated them with hyaluronic acid to create a sustainable ROS generator. This nanomaterial could be evenly distributed throughout the entire tumor. In reaction to the TME, MC undergoes degradation, producing Mn²⁺ that facilitates the sustained transformation of H₂O₂ generated during PDT into the highly deleterious ROS. This process intensifies the cytotoxic effects on the tumor. For their study, they selected 4T1 mouse breast cancer cells expressing high levels of GSH as the tumor model cells. They also utilized Hs578Bst human normal breast cells with low GSH expression as control cells to confirm the higher tumor selectivity of Mn₃O₄-Ce6 nanoparticles. The outcomes demonstrated a substantial decrease in both tumor volume and weight in the group treated with MnNMs. Moreover, the tumor tissues displayed more extensive damage when compared to other treatment groups, as evidenced by H&E staining.

Combining manganese nanomaterials with suitable metal materials can provide higher photothermal conversion efficiency. In 2020, Zhu et al. reported manganese nanomaterials BSA-Ce6@IrO₂/MnO₂ with a remarkable photothermal conversion rate of up to 65.3% (Wu et al., 2020). Ce6 serves as a photosensitizer, while IrO₂ and MnO₂ act as catalysts to improve the TME, decompose endogenous H₂O₂ to generate oxygen (O₂), thereby enhancing the efficacy of PDT. Simultaneously, the released Mn²⁺ from the composite material can serve as a contrast agent for MRI.

In general, MnNMs demonstrate promising applications in PDT by improving the hypoxic TME and enhancing the generation of ROS. Furthermore, their combination with other suitable metal materials and photosensitizers may yield additional surprising performances.

CDT, based on Fenton or Fenton-like reactions, transforms H₂O₂ into highly toxic hydroxyl radical (•OH) to selectively eliminate tumor cells (Jana and Zhao, 2022). This method was first introduced by Bu, Shi, and their team in 2016 (Zhang et al., 2016). Nevertheless, the high levels of antioxidants in the TME, including GSH, have impeded the clinical translation of this strategy. These antioxidants scavenge ROS to maintain cellular redox homeostasis, thereby substantially reducing the effectiveness of CDT (Cheung and Vousden, 2022). Fortunately, MnNMs possess a strong ability to deplete intracellular antioxidants like GSH. They preferentially accumulate in tumor sites due to EPR, utilizing Fenton-like reactions (Gu et al., 2021; Gao et al., 2022), thereby annihilating tumors.

In 2022, the Liu research team utilized the microemulsion method to synthesize manganese-doped Prussian blue nanoparticles (MnPB NPs) (Tao et al., 2022). Due to the incorporation of Mn²⁺, MnPB NPs demonstrated robust catalytic activity, efficiently converting H₂O₂ into •OH through the Fenton reaction. Experimental findings from both in vitro and in vivo studies indicated that MnPB NPs-mediated CDT exhibited excellent tumor-killing efficacy. MnNMs can synergistically enhance CDT in conjunction with other metallic nanomaterials.

In another study, the research team led by Hu developed a versatile biomimetic nanozyme, Se@SiO₂-Mn@Au/DOX (SSMA/DOX) (Zheng et al., 2022). This nanozyme exhibits responsive degradation in the acidic TME, producing Mn²⁺ as a byproduct. Mn²⁺ not only enables therapeutic monitoring through MRI imaging but also catalyzes the conversion of endogenous H₂O₂ into •OH for CDT (Figure 7) (Zheng et al., 2022). Additionally, Au NPs catalyze glucose to provide the required H₂O₂ for CDT.

In summary, manganese nanomaterials lay the foundation for enhancing CDT by degrading within the TME to generate Mn²⁺, thereby initiating Fenton-like reactions. The integration of manganese nanomaterials with other substances or treatment modalities offers expanded possibilities for their synergistic effectiveness.

SDT is a therapeutic approach that employs low-intensity ultrasound to stimulate sonosensitizers, inducing the generation of reactive oxygen species within tumor cells, thereby leading to the destruction of tumor cells (Pan et al., 2018). It was first introduced by Umemura and colleagues in 1990 (Umemura et al., 1990; Yumita et al., 1990). The selection of suitable sonosensitizers is essential for the efficacy of SDT (Son et al., 2020). Manganese-based nanoscale sonosensitizers, in comparison to traditional organic counterparts, the capability to catalyze H₂O₂ molecules for the conversion into O₂ is instrumental in enhancing SDT.

Li et al. have fabricated nanostructured materials by loading manganese oxide (MnOx) onto piezoelectric bismuth oxychloride nanosheets (BiOCl NS), resulting in M-BOC@SP NSs. The piezotronic effect of BiOCl NS serves as a sound sensitizer. Leveraging the diverse enzymatic-like activities of MnOx, M-BOC@SP NSs not only downregulate the levels of GSH in the TME but also facilitate the decomposition of intracellular H₂O₂ into O₂ and •OH. This process stimulates the production of ROS and reverses hypoxia, thereby enhancing SDT.

The combination of manganese nanoparticle with organic sonosensitizers also can enhances the efficacy of SDT (Zhu et al., 2018b; Chen et al., 2022b). In 2022, the Niu research team developed IR780/poly (lactide-co-glycolide) (PLGA)@MnO₂ nanomaterials (Xu et al., 2022). IR780 served as the sonosensitizer, and PLGA was employed to enhance the biocompatibility and stability of IR780. The MnO₂ nanocoating not only prevented the premature release of IR780 in the bloodstream, enhancing the stability of IR780/PLGA nanomaterials, but also responded to the acidic TME, degrading in acidic conditions to produce O₂. Upon degradation of MnO₂, IR780 is released in the tumor, promoting the generation of ROS and enhancing SDT (Figure 8) (Xu et al., 2022). And mn²⁺ can enhance the signal intensity of MRI.

MnNMs primarily enhance SDT by catalyzing the decomposition of H₂O₂ into O₂ within the tumor. When combined with suitable sonosensitizers, MnNMs can also elicit additional effects, such as enhancing ferroptosis and inducing immunogenic cell death (Xu et al., 2021b; Chen et al., 2021). This demonstrates the great potential of manganese nanomaterials in sonodynamic cancer therapy.

In recent years, there has been rapid advancement in the field of immunetherapy, which stands as a potent therapeutic modality for cancer (Dagher et al., 2023). Unlike traditional methods such as surgery, chemotherapy, radiation therapy, and targeted treatment, immunotherapy works by stimulating and enhancing the inherent anti-tumor immune functions to suppress and eliminate cancer cells (Yang et al., 2023). Through the combination with nanomaterials, immunotherapy presents the potential for personalized and precise cancer treatment strategies (Martin et al., 2020).

Similar to most nanomaterials, MnNMs can serve as carriers for delivering immunotherapeutic agents, preventing premature degradation of the immunotherapeutic agents. In 2022, the Shen research team engineered TME-responsive nanomaterials by employing MnO₂-albumin as a drug carrier, loaded with the PD-L1 inhibitor Butformin (Bu) and the PD-1 inhibitor Methylene Blue (MB), resulting in the preparation of the MB@Bu@MnO₂ nanomaterial (Zhou et al., 2022). The MnO₂ nanomaterial selectively delivers the drugs, preventing premature release of MB and Bu. Upon reaching the tumor site, the acidic TME triggers the degradation of MnO₂, leading to rapid drug release. MnO₂-mediated O₂ generation further enhances PDT, subsequently downregulating PD-L1 expression and inhibiting PD-1 activation.

MnNMs also play a role in enhancing anti-tumor immune responses by improving the hypoxic TME (Liang et al., 2018; Luo et al., 2023). In 2021, M. Adjei and colleagues encapsulated MnO₂ in PLGA to create PLGA-MnO₂NPs (Murphy et al., 2021). Within the tumor, PLGA-MnO₂NPs catalyze the generation of oxygen from H₂O₂, leading to an improvement in the function of NK cells due to the amelioration of the hypoxic microenvironment. In the situation of PLGA-MnO₂ NP-induced changes in the TME, NK cells effectively enhance IFN-γ production, and the heightened cytotoxicity against tumor cells is confirmed through Lactate dehydrogenase assay. This suggests that PLGA-MnO₂NPs can promote tumor immunotherapy by facilitating oxygen production.

In recent years, extensive research has indicated that Mn²⁺ can serve as a cGAS-STING agonist, enhancing tumor immunotherapy (Lv et al., 2020; Wang et al., 2022a). Therefore, MnNMs have garnered increasing attention in the field of tumor immunotherapy (Zheng et al., 2023b; Cheng et al., 2023).

In 2022, Hou et al. combined hollow mesoporous SiO₂-coated MnO nanoparticles with the tumor homing peptide iRGD, constructing MnO@mSiO₂-iRGD NPs (Sun et al., 2022). MnO@mSiO₂-iRGD NPs accumulate in tumors through active targeting facilitated by iRGD and respond to the acidic TME, resulting in the decomposition of MnO and the generation of Mn²⁺, enhancing T1-weighted MRI. Upon injecting MnO@mSiO₂-iRGD nanomaterials into mice, a noticeable upregulation of STING was observed (Figure 9) (Sun et al., 2022). Furthermore, when MnO@mSiO₂-iRGD and α-PD-1 antibody were used in combination for tumor treatment, the number of CD8⁺ T cells in the tumor tissue significantly increased compared to the use of α-PD-1 antibody alone.

In conclusion, manganese nanostructures can enhance tumor immunotherapy by delivering immunotherapeutic drugs and modulating the tumor immune microenvironment to promote immune responses. Furthermore, the degradation of manganese nanostructures in response to the TME, leading to the release of Mn²⁺ and activation of the cGAS-STING pathway, is being extensively researched as a mechanism to trigger tumor immunotherapy.