Manganese Dioxide Nanoparticles Research Articles

Exosome membrane-sheathed and multi-stimuli-responsive MnO2 nanoparticles with self-oxygenation and energy depletion abilities potentiate the sonodynamic therapy of hypoxic tumors

Sonodynamic therapy (SDT), which employs ultrasound (US) to activate sonosensitizers to generate reactive oxygen species (ROS), has emerged as an effective approach for treating deep-seated tumors. However, poor biocompatibility of sonosensitizers and hypoxic tumor microenvironments are significant challenges for in vivo SDT. Herein, hollow manganese dioxide nanoparticles (MnO2 NPs) encapsulating the sonosensitizer, indocyanine green (ICG), were developed for enhanced sonodynamic cancer therapy by high ICG loading and tumor hypoxia relief. A glycolysis inhibitor, FX11, was co-loaded into MnO2 NPs to boost SDT efficacy via FX11-induced energy depletion. Because of the high biocompatibility, low immunogenicity, and efficient intracellular delivery of exosomes, ICG- and FX11-loaded MnO2 NP [M(ICG/FX11)] was coated with exosome membranes for safe and efficient in vivo SDT. The exosome membrane-coated M(ICG/FX11) [Exo-M(ICG/FX11)] exhibited triple pH/H2O2/US-responsive drug release while avoiding premature drug leakage. Exo-M(ICG/FX11) was efficiently internalized by MCF-7 human breast cancer cells and catalyzed the endogenous H2O2 to generate O2 to relieve tumor hypoxia. Consequently, Exo-M(ICG/FX11) markedly boosted intracellular ROS levels upon US irradiation. Moreover, Exo-M(ICG/FX11) effectively inhibited glycolytic pathways, thereby potentiating the anticancer efficacy of SDT. An in vivo study using tumor-xenografted mice demonstrated that Exo-M(ICG/FX11) effectively accumulated in tumors and alleviated tumor hypoxia. Notably, Exo-M(ICG/FX11) combined with US substantially suppressed tumors in mice without causing systemic toxicity, owing to the synergistic effect of O2 supplied-SDT and energy-depleting chemotherapy. This study demonstrates that biomimetic Exo-M(ICG/FX11) is a safe and efficient nanoplatform for the treatment of hypoxic tumors.

Record-High Ultrasound-Sensitive NO Nanogenerators for Cascade Tumor Pyroptosis and Immunotherapy.

Pyroptosis is a pro-inflammatory cell death that is associated with innate immunity promotion against tumors. Excess nitric oxide (NO)-triggered nitric stress has potential to induce pyroptosis, but the precise delivery of NO is challenging. Ultrasound (US)-responsive NO production has dominant priority due to its deep penetration, low side effects, noninvasion, and local activation manner. In this work, US-sensitive NO donor N-methyl-N-nitrosoaniline (NMA) with thermodynamically favorable structure is selected and loaded into hyaluronic acid (HA)-modified hollow manganese dioxide nanoparticles (hMnO2 NPs) to fabricate hMnO2 @HA@NMA (MHN) nanogenerators (NGs). The obtained NGs have a record-high NO generation efficiency under US irradiation and can release Mn2+ after targeting the tumor sites. Later on, cascade tumor pyroptosis and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-based immunotherapy is achieved and tumor growth is effectively inhibited.

Photo-catalytic Degradation of Ciprofloxacin using Manganese and Cobalt Co-Doped Titanium Dioxide Nanoparticles (Mn-Co-TiO2)

Photo-catalytic Degradation of Ciprofloxacin using Manganese and Cobalt Co-Doped Titanium Dioxide Nanoparticles (Mn-Co-TiO2)

Transferrin-Conjugated Manganese Dioxide/Semiconducting Polymer Hybrid Nanoparticles for Targeted Dual-Model Imaging of Orthotopic Glioblastoma

Glioblastoma is one of the important diseases that threaten human health, while the early diagnosis of glioblastoma remains a great challenge. We herein report the development of transferrin (Tf)-conjugated hybrid nanoparticles for targeted magnetic resonance (MR) and near-infrared (NIR) fluorescence dual-model imaging of orthotopic glioblastoma in living mouse models. Tf-stabilized manganese dioxide (MnO2) nanoparticles were conjugated onto the surface of semiconducting polymer nanoparticles (SPNs) to allow the formation of hybrid nanoparticles (Tf@SPNM). Due to the surface modification of Tf that could bind to the Tf receptor, Tf@SPNM would overcome the blood–brain barrier (BBB) and target the glioblastoma cells, which resulted in a more effective delivery of Tf@SPNM into orthotopic glioblastoma sites compared to that of their control nanoparticles. In view of the high r1 relaxation (9.8 mM–1 s–1) and bright NIR fluorescence emission, Tf@SPNM could achieve MR and NIR fluorescence dual-model imaging of orthotopic glioblastoma with obviously improved imaging contrast. Thus, this study provides a multifunctional hybrid nanoplatform for effective diagnosis of orthotopic glioblastoma.

In situ photo-crosslinking silk fibroin based hydrogel accelerates diabetic wound healing through antibacterial and antioxidant

Bacterial infection and excessive reactive oxygen species (ROS) in diabetic wounds lead to a prolonged inflammatory phase, and injuries are highly susceptible to developing into chronic wounds. Improving the poor microenvironment is vital to achieving effective diabetic wound healing. In this work, methacrylated silk fibroin (SFMA) was combined with ε-polylysine (EPL) and manganese dioxide nanoparticles (BMNPs) to form an SF@(EPL-BM) hydrogel with in situ forming, antibacterial and antioxidant properties. EPL imparted high antibacterial activity (>96 %) to the hydrogel. BMNPs and EPL showed good scavenging activity against a variety of free radicals. SF@(EPL-BM) hydrogel had low cytotoxicity and could alleviate H2O2-induced oxidative stress in L929 cells. In diabetic wounds infected with Staphylococcus aureus (S. aureus), the SF@(EPL-BM) hydrogel exhibited better antibacterial properties and reduced wound ROS levels more significantly than that of the control in vivo. In this process, the pro-inflammatory factor TNF-α was down-regulated, and the vascularization marker CD31 was up-regulated. H&E and Masson staining showed a rapid transition from the inflammatory to the proliferative phase of the wounds, with significant new tissue and collagen deposition. These results confirm that this multifunctional hydrogel dressing holds well potential for chronic wound healing.

Transcriptomics-based investigation of manganese dioxide nanoparticle toxicity in rats’ choroid plexus

Manganese dioxide nanoparticles (MnO2-NPs) have a wide range of applications in biomedicine. Given this widespread usage, it is worth noting that MnO2-NPs are definitely toxic, especially to the brain. However, the damage caused by MnO2-NPs to the choroid plexus (CP) and to the brain after crossing CP epithelial cells has not been elucidated. Therefore, this study aims to investigate these effects and elucidate potential underlying mechanisms through transcriptomics analysis. To achieve this objective, eighteen SD rats were randomly divided into three groups: the control group (control), low-dose exposure group (low-dose) and high-dose exposure group (high-dose). Animals in the two treated groups were administered with two concentrations of MnO2-NPs (200 mg kg−1 BW and 400 mg kg−1 BW) using a noninvasive intratracheal injection method once a week for three months. Finally, the neural behavior of all the animals was tested using a hot plate tester, open-field test and Y-type electric maze. The morphological characteristics of the CP and hippocampus were observed by H&E stain, and the transcriptome of CP tissues was analysed by transcriptome sequencing. The representative differentially expressed genes were quantified by qRT-PCR. We found that treatment with MnO2-NPs could induce learning capacity and memory faculty decline and destroy the structure of hippocampal and CP cells in rats. High doses of MnO2-NPs had a more obvious destructive capacity. For transcriptomic analysis, we found that there were significant differences in the numbers and types of differential genes in CP between the low- and high-dose groups compared to the control. Through GO terms and KEGG analysis, high-dose MnO2-NPs significantly affected the expression of transporters, ion channel proteins, and ribosomal proteins. There were 17 common differentially expressed genes. Most of them were transporter and binding genes on the cell membrane, and some of them had kinase activity. Three genes, Brinp, Synpr and Crmp1, were selected for qRT-PCR to confirm their expression differences among the three groups. In conclusion, high-dose MnO2-NPs exposure induced abnormal neurobehaviour, impaired memory function, destroyed the structure of the CP and changed its transcriptome in rats. The most significant DEGs in the CP were within the transport system.

Superior electronic/ionic transport dynamics of Zn-Co-OH/MnO2 heterointerface containing oxygen vacancies for pseudocapacitive storage

The superior electronic/ionic transport dynamics of electrode materials have been crucial to achieve appealing high performance for supercapacitors. Herein, a fascinating one-dimensional (1D) zinc cobalt hydroxide nanobelts/0D irregular manganese dioxide nanoparticles (M-ZCOH) have been vertically loaded into the 3D Ni foam (NF) substrate wrapped by nitrogen-doped graphene (NPG) (M-ZCOH/NPG/NF) for supercapacitors. The ingeniously designed M-ZCOH/NPG/NF composites feature powerful built-in electric field (BIEF) introduced by well-defined heterointerface with abundant oxygen vacancies defects. The formed electron accumulation triggering strong interfacial interaction verified by the differential charge density analysis may endow M-ZCOH/NPG/NF with the extra driving force to increase the diffusion/adsorption of electrolyte ions, thereby facilitating electron/ion transfer kinetics. Also, the qualitative negative shift of the d band center for M-ZCOH composites further evidences a lower electron/ion transfer barrier compared with the monomers. Obviously, the penetrating understanding of heterointerface on the improved properties is manifestly interpreted by combining theoretical and experimental analysis. Moreover, the ingenious strategy of engineering the heterointerfaces in unique heterostructure with rich defects may provide a new prospect for optimizing other advanced materials in sustainable energy storage systems.

Trace N-doped manganese dioxide cooperated with Ping-pong chrysanthemum-like NiAl-layered double hydroxide on cathode for improving bioelectrochemical performance of microbial fuel cell

Trace N-doped manganese dioxide (MnO2) nanoparticles were attached to NiAl-layered double hydroxide (LDH) nano sheets by a simple two-step hydrothermal reaction, and N-MnO2@NiAl-LDH was successfully prepared as cathode catalyst of microbial fuel cell (MFC). N-MnO2@NiAl-LDH was Ping-pong chrysanthemum-like structure formed by overlapping lamellar structures, with spherical MnO2 particles attached on. The unique Ping-pong chrysanthemum-like structure and pore size distribution provided large number of electrochemical active sites. The recombination of trace N and MnO2 reduced the charge transfer resistance, accelerated the electron transfer rate, and N-MnO2@NiAl-LDH showed high oxygen reduction reaction (ORR) capability. The maximum output power density of N-MnO2@NiAl-LDH-MFC was 698 mW/m2, about 4.59 times of NiAl-LDH (152.1 mW/m2). The maximum voltage was about 320 mV, and the stability was good for about 7 d. This would provide technical reference for the utilization of cathode catalyst for fuel cells.

New insights on manganese dioxide nanoparticles loaded on cellulose-based biochar of cassava peel for the adsorption of three cationic dyes from wastewater

Herein, a cost-effective nanomaterial with excellent adsorption capacity, simply prepared, using manganese dioxide (MnO2) nanoparticles (NP) loaded on cellulose-based biochar of an agricultural waste, which is cassava peel carbon (CPC) and denoted as MnO2-NP-CPC. MnO2-NP-CPC is an environmental-friendly, and efficient adsorbent analyzed using different technics such as x-ray diffraction (XRD), Fourier-transformed infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and energy dispersive x-ray spectroscopy (EDX). MnO2-NP-CPC was used to remove three different toxic dyes; methylene blue (MB), malachite green (MG), and rhodamine b (RB) from a single (MB), (MG), (RB), binary (MB + MG), (MG + RB), (MB + RB) and ternary (MB + MG + RB) wastewater systems, the impact of pH, adsorbent dose (2–8), initial dye concentrations (10–30 mg/L), temperature (15–35 °C) were fully studied. Furthermore, all the sorption experiments were done including adsorption isotherms, kinetics, and thermodynamics to explore all the mechanisms involved in the sorption of the three ionic dyes in single, binary, and ternary systems. The equilibrium experiments data fitted well the monolayer Langmuir isotherm for the single dye system with correlation coefficients close to 1 (0.98 for MB, 0.99 for MG, and 0.86 for RB), while the extended Langmuir and extended Freundlich isotherms were investigated to study the interaction of the three dyes in their binary systems, the obtained results indicate clearly that the sorption fellows the extended Langmuir model. Besides, the kinetic study showed the applicability of the pseudo-second model for the three dyes. Finally, the thermodynamic adsorption was controlled by physisorption, endothermic, and spontaneous in nature.

Green synthesis of manganese dioxide nanoparticles: photocatalytic and antimicrobial investigations

ABSTRACT In the present study, we report the green synthesis of manganese dioxide (MnO2) nanoparticles using Lyngbya Majuscula by the single-step co-precipitation method. The green synthesised MnO2 nanoparticles were characterised by a mix of microscopy, and spectroscopic methods such as X-Ray diffraction analysis, Fourier transform infrared Spectroscopy, Field emission scanning electron microscope, and High-Resolution Transmission Electron Microscopy, analysis. The photocatalytic degradation ability of the as-prepared sample was investigated against the methylene blue (MB) dye under different light sources such as LED, UV, and sunlight irradiation. According to the photocatalytic degradation analysis, the green synthesised MnO2 nanoparticles show high photocatalytic degradation under UV light irradiation. Similarly, the antibacterial activity of the green synthesised MnO2 nanoparticles are investigated against the Trichodermaviride, Micrococcus Luteus, Staphylococcus Aureus, Aspergillus Niger, and Pseudomonas Aeruginosa. Furthermore, the green synthesised MnO2 nanoparticles show high efficacy of the agar well diffusion method in eradicating dangerous microorganisms.

Influence of Manganese Dioxide Nanoparticles on MoS2/PANI Nanosheets and Its Energy Storage Applications

Influence of Manganese Dioxide Nanoparticles on MoS2/PANI Nanosheets and Its Energy Storage Applications

Chemotaxis-guided Self-propelled Macrophage Motor for Targeted Treatment of Acute Pneumonia.

Immune cells exhibit great potential as carriers of nanomedicine, attributed to their high tolerance to internalized nanomaterials and targeted accumulation in inflammatory tissues. However, the premature efflux of internalized nanomedicine during systemic delivery and slow infiltration into inflammatory tissues have limited their translational applications. Herein, a motorized cell platform as a nanomedicine carrier for highly efficient accumulation and infiltration in the inflammatory lungs and effective treatment of acute pneumonia are reported. β-Cyclodextrin and adamantane respectively modified manganese dioxide nanoparticles are intracellularly self-assembled into large aggregates mediated via host-guest interactions, to effectively inhibit the efflux of nanoparticles, catalytically consume/deplete H2 O2 to alleviate inflammation, and generate O2 to propel macrophage movement for rapid tissue infiltration. With curcumin loaded into MnO2 nanoparticles, macrophages carry the intracellular nano-assemblies rapidly into the inflammatory lungs via chemotaxis-guided, self-propelled movement, for effective treatment of acute pneumonia via immunoregulation induced by curcumin and the aggregates.

Plant-assisted synthesis and characterization of MnO2 nanoparticles for removal of crystal violet dye: an environmental remedial approach.

The current study is focused on the use of the Caryota mitis Lour. (Fishtail palm) flower extract as a reducing agent for the preparation of manganese dioxide (MnO2) nanoparticles. Scanning electron microscopy (SEM), four-phase infrared analysis (FT-IR), and x-ray diffraction (XRD) methods were used to characterize the MnO2 nanoparticles. The nature of MnO2 nanoparticles was revealed by an absorption peak at 590nm in a spectrophotometer (A1000). Then, these MnO2 nanoparticles were applied to decolorize the crystal violet dye. At 0.004% dye concentration, pH 4, and concentration of MnO2 nanoparticles of 0.005g/L at temperatures of 50°C, the target dye was decolorized by 91.3%. Percent reductions in COD and TOC were found to be 92.1% and 90.6%, respectively. Finally, the dye decolorization pathway was proposed based on the experimental findings.

Phytic acid-modified manganese dioxide nanoparticles oligomer for magnetic resonance imaging and targeting therapy of osteosarcoma

Osteosarcoma is the most common malignant tumor in the skeletal system with high mortality. Phytic acid (PA) is a natural compound extracted from plant seeds, which shows certain antitumor activity and good bone targeting ability. To develop a novel theranostics for magnetic resonance imaging (MRI) and targeting therapy of osteosarcoma, we employed PA to modify manganese dioxide nanoparticles (MnO2@PA NPs) for osteosarcoma treatment. The MnO2 NPs oligomer was formed by PA modification with uniformed size distribution and negative zeta potential. Fourier-transform infrared spectroscopy, X-ray diffraction, energy dispersive spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis demonstrated that PA has been successfully modified on MnO2 NPs, and the structure of MnO2@PA NPs is amorphous. In vitro experiments demonstrated that MnO2@PA NPs oligomer can be efficiently internalized by tumor cell, and the internalized NPs can react with H2O2 under acid microenvironment to produce Mn2+ and O2. In vivo experiments demonstrated that MnO2@PA NPs oligomer can passively accumulate in tumor tissue, and the accumulated NPs can produce Mn2+ and O2 for MRI and targeting therapy of osteosarcoma. In conclusion, we prepared a novel bone-targeting nano theranostics for MRI and therapy of osteosarcoma.

Immunomodulatory activity of manganese dioxide nanoparticles: Promising for novel vaccines and immunotherapeutics.

Manganese (Mn), a nutrient inorganic trace element, is necessary for a variety of physiological processes of animal body due to their important roles in oxidative regulation effects and other aspects of activities. Moreover, manganese ion (Mn2+) has widely reported to be crucial for the regulations of different immunological responses, thus showing promising application as potential adjuvants and immunotherapeutics. Taking the advantages of Mn-based biological and immunological activities, Manganese dioxide nanoparticles (MnO2 NPs) are a new type of inorganic nanomaterials with numerous advantages, including simple preparation, low cost, environmental friendliness, low toxicity, biodegradable metabolism and high bioavailability. MnO2 NPs, as a kind of drug carrier, have also shown the ability to catalyze hydrogen peroxide (H2O2) to produce oxygen (O2) under acidic conditions, which can enhance the efficacy of radiotherapy, chemotherapy and other therapeutics for tumor treatment by remodeling the tumor microenvironment. More importantly, MnO2 NPs also play important roles in immune regulations both in innate and adaptive immunity. In this review, we summarize the biological activities of Manganese, followed by the introduction for the biological and medical functions and mechanisms of MnO2 NPs. What's more, we emphatically discussed the immunological regulation effects and mechanisms of MnO2 NPs, as well as their potentials to serve as adjuvants and immunomodulators, which might benefit the development of novel vaccines and immunotherapies for more effective disease control.

Hypoxia-ameliorated photothermal manganese dioxide nanoplatform for reversing doxorubicin resistance.

Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO2) nanoparticles (BSA/MnO2 NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO2 NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO2 NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO2 NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO2 NPs can interact with H2O2 and H+ in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO2, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO2 platform is a promising strategy for revering DOX resistance.

Brain-Penetrating and Disease Site-Targeting Manganese Dioxide-Polymer-Lipid Hybrid Nanoparticles Remodel Microenvironment of Alzheimer's Disease by Regulating Multiple Pathological Pathways.

Finding effective disease-modifying treatment for Alzheimer's disease remains challenging due to an array of factors contributing to the loss of neural function. The current study demonstrates a new strategy, using multitargeted bioactive nanoparticles to modify the brain microenvironment to achieve therapeutic benefits in a well-characterized mouse model of Alzheimer's disease. The application of brain-penetrating manganese dioxide nanoparticles significantly reduces hypoxia, neuroinflammation, and oxidative stress; ultimately reducing levels of amyloid β plaques within the neocortex. Analyses of molecular biomarkers and magnetic resonance imaging-based functional studies indicate that these effects improve microvessel integrity, cerebral blood flow, and cerebral lymphatic clearance of amyloid β. These changes collectively shift the brain microenvironment toward conditions more favorable to continued neural function as demonstrated by improved cognitive function following treatment. Such multimodal disease-modifying treatment may bridge critical gaps in the therapeutic treatment of neurodegenerative disease.

Nucleus-Targeting Manganese Dioxide Nanoparticles Coated with the Human Umbilical Cord Mesenchymal Stem Cell Membrane for Cancer Cell Therapy.

Recently, development of drug delivery systems for accurate delivery of antitumor drugs to tumor sites to improve their antitumor efficacy has attracted great interest in the area of cancer immunotherapy. In this report, an intelligent biodegradable hollow manganese dioxide (HMnO2) nanoparticle (NP) with a human umbilical cord mesenchymal stem cell (hUC-MSC) membrane coating was designed to exert efficient chemo-immunotherapy for cancer treatment. A TAT peptide-modified membrane structure was constructed for nuclear targeting. Our findings showed that this new nanoreactor inherited the active targeting capability of MSCs and exhibited tumoritropic accumulation significantly at the cancerous parts. Compared with other formulations, intravenous injection of the NPs markedly inhibited tumor growth, relapse, and metastasis. Moreover, we found that the NPs effectively boosted dendritic cell maturation and recruited effector T cells into tumors. Overall, this work demonstrates the great potential of applying MSC membrane-coated manganese dioxide NPs as nucleus-targeting nanocarriers in cancer chemo-immunotherapy.

Engineering a polymer-encapsulated manganese dioxide/upconversion nanoprobe for FRET-based hydrogen peroxide detection.

Hydrogen peroxide (H2O2) is considered a significant biomarker in various diseases and could induce deleterious health problems at irregular physiological concentrations. Therefore, developing a simple, efficient biocompatible nanoprobe for trace amount H2O2 detection with high sensitivity and specificity is of great help for early diagnosis and therapeutics. Herein, we designed amphiphilic poly(styrene-co-maleic anhydride) (PMSA)-encapsulated nanoclusters composed of upconversion nanoparticles (UCNPs) and manganese dioxide nanoparticles (MnO2 NPs) at a specific ratio to produce a near-infrared (NIR) excited luminescent nanoprobe for H2O2 detection. Our results revealed that the MnO2 NPs tended to experience catalytic decomposition when exposed to H2O2, while the UCNPs were retained inside the PSMA encapsulation, causing recovery of the UCNP emission band at 470nm in accordance with H2O2 concentration. This luminescence recovery was linearly dependent on H2O2 concentrations, yielding a limit of detection (LOD) of 20nM. The easy-to-interpret H2O2 nanoprobe also proved high selectivity in the presence of other interfering substances, and biocompatibility and water-dispersibility, making it an ideal candidate for real-time detection of disease-related H2O2 in living organisms.

Dual-Cascade Activatable Nanopotentiators Reshaping Adenosine Metabolism for Sono-Chemodynamic-Immunotherapy of Deep Tumors.

Immunotherapy is an attractive treatment strategy for cancer, while its efficiency and safety need to be improved. A dual-cascade activatable nanopotentiator for sonodynamic therapy (SDT) and chemodynamic therapy (CDT)-cooperated immunotherapy of deep tumors via reshaping adenosine metabolism is herein reported. This nanopotentiator (NPMCA ) is constructed through crosslinking adenosine deaminase (ADA) with chlorin e6 (Ce6)-conjugated manganese dioxide (MnO2 ) nanoparticles via a reactive oxygen species (ROS)-cleavable linker. In the tumor microenvironment with ultrasound (US) irradiation, NPMCA mediates CDT and SDT concurrently in deep tumors covered with 2-cm tissues to produce abundant ROS, which results in dual-cascade scissoring of ROS-cleavable linkers to activate ADA within NCMCA to block adenosine metabolism. Moreover, immunogenic cell death (ICD) of dying tumor cells and upregulation of the stimulator of interferon genes (STING) is triggered by the generated ROS and Mn2+ from NPMCA , respectively, leading to activation of antitumor immune response. The potency of immune response is further reinforced by reducing the accumulation of adenosine in tumor microenvironment by the activated ADA. As a result, NPMCA enables CDT and SDT-cooperated immunotherapy, showing an obviously improved therapeutic efficacy to inhibit the growths of bilateral tumors, in which the primary tumors are covered with 2-cm tissues.