A manganese dioxide nanoparticle-bimetallic metal organic framework composite for selective and sensitive detection of vitamin D3 in human plasma.

For the first time a metal organic framework nanomaterial has been developed comprising manganese dioxide nanoparticle and iron and zinc metal ions interlinked with each other via terephthalic acid. The framework shape was identified as an elongated hexagonal nanorod (TEM) with varying functional groups (FT-IR) and diffraction patterns (XRD). The framework nanocomposite as such in aqueous acidic electrolyte solution has displayed an excellent conductivity (redox behavior) and surface excess (3.08 × 10-8 cm-2). Under the optimized conditions (0.1 M H2SO4 as electrolyte, 50 mV/s scan rate, +1.26 V (vs Ag/AgCl)), the metal organic framework coated electrode has selectively identified vitamin D3 (VD3) in the presence of various other interfering molecules and displayed excellent limit of detection (1.9 ng mL-1). The developed sensor has been applied to the determination of VD3 in extracted human plasma samples (RSD of 0.3-2.6 % and recovery of 96-102 %), and the obtained VD3 values are similar to HPLC-UV method.

Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy.

BACKGROUND: Although lower temperature (< 45 °C) photothermal therapy (LPTT) have attracted enormous attention in cancer therapy, the therapeutic effect is still unsatisfying when applying LPTT alone. Therefore, combining with other therapies is urgently needed to improve the therapeutic effect of LPTT. Recently reported oxygen-irrelevant free radicals based thermodynamic therapy (TDT) exhibit promising potential for hypoxic tumor treatment. However, overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy. METHODS AND RESULTS: In this work, a core-shell nanoplatform with an appropriate size composed of arginine-glycine-aspartate (RGD) functioned polydopamine (PDA) as a shell and a triphenylphosphonium (TPP) modified hollow mesoporous manganese dioxide (H-mMnO2) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO2 and thickness-tunable PDA layers, which effectively prevented the pre-matured release of encapsulated azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI) and revealed pH/NIR dual-responsive release performance. With the mitochondria-targeting ability of TPP, the smart nanocomposites (AIBI@H-mMnO2-TPP@PDA-RGD, AHTPR) could efficiently induce mitochondrial associated apoptosis in cancer cells at relatively low temperatures (< 45 °C) via selectively releasing oxygen-irrelevant free radicals in mitochondria and facilitating the depletion of intracellular GSH, exhibiting the advantages of mitochondria-targeted LPTT/TDT. More importantly, remarkable inhibition of tumor growth was observed in a subcutaneous xenograft model of osteosarcoma (OS) with negligible side effects. CONCLUSIONS: The synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo. Additionally, the excellent biosafety and biocompatibility of the nanoplatforms were confirmed both in vitro and in vivo. Taken together, the current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors.

Catechol-Modified and MnO2-Nanozyme-Reinforced Hydrogel with Improved Antioxidant and Antibacterial Capacity for Periodontitis Treatment.

Periodontitis is an inflammatory disease characterized by tooth loss and alveolar bone resorption. Bacteria are the original cause of periodontitis, and excess reactive oxygen species (ROS) encourage and intensify inflammation. In this study, a mussel-inspired and MnO2 NPs-reinforced adhesive hydrogel capable of alleviating periodontitis with improved antibacterial and antioxidant abilities was developed. The hydrogel was created by combining polyvinyl alcohol (PVA), 3,4-dihydroxy-d-phenylalanine (DOPA), and MnO2 nanoparticles (NPs) (named PDMO hydrogel). The hydrogel was demonstrated to be able to scavenge various free radicals (including total ROS─O2•- and OH•) and relieve the hypoxia in an inflammatory microenvironment by scavenging excess ROS and generating O2 due to its superoxide dismutase (SOD)/catalase (CAT)-like activity. Besides, under 808 nm near-infrared (NIR) light, the photothermal performance of the PDMO hydrogel displayed favorable antibacterial and antibiofilm effects toward Escherichia coli, Staphylococcus aureus, and Porphyromonas gingivalis (up to nearly 100% antibacterial rate). Furthermore, the PDMO hydrogel exhibited favorable therapeutic efficacy in alleviating gingivitis in Sprague-Dawley rats, even comparable to or better than the commercial PERIO. In addition, in the periodontitis models, the PDMO2 group showed the height of the residual alveolar bone and the smallest shadow area of low density among other groups, indicating the positive role of the PDMO2 hydrogel in bone regeneration. Finally, the biosafety of the PDMO hydrogel was comprehensively investigated, and the hydrogel was demonstrated to have good biocompatibility. Therefore, the developed PDMO hydrogel provided an effective solution to resolve biofilm recolonization and oxidative stress in periodontitis and could be a superior candidate for local drug delivery system in the clinical management of periodontitis with great potential for future clinical translation.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Metal-polyphenol nanodots loaded hollow MnO2 nanoparticles with a "dynamic protection" property for enhanced cancer chemodynamic therapy.

Chemodynamic therapy (CDT) is a novel cancer therapeutic strategy. However, barriers such as high glutathione (GSH) concentration and low concentration of metal ions intracellular reduce its treatment effect. In this work, a nanosystem named GA-Fe@HMDN-PEI-PEG with a "dynamic protection" property was reported for enhanced cancer CDT. Mesoporous hollow manganese dioxide (MnO2) nanoparticle (HMDN) was prepared to load gallic acid-ferrous (GA-Fe) nanodots fabricated from gallic acid (GA) and ferrous ion (Fe2+). Then the pores of HMDN were blocked by polyethyleneimine (PEI), which was then grafted with methoxy poly(ethylene glycol) (mPEG) through a pH-sensitive benzoic imine bond. mPEG could protect the nanoparticles (NPs) against the nonspecific uptake by normal cells and enhance their accumulation in the tumor. However, in the slightly acidic tumor microenvironment, hydrolysis of benzoic imine led to DePEGylation to reveal PEI for enhanced uptake by cancer cells. The reaction between HMDN and GSH could consume GSH and obtain manganese ion (Mn2+) for the Fenton-like reaction for CDT. GA-Fe nanodots could also offer Fe for the Fenton reaction, and reductive GA could reduce the high-valence ions to low-valence for reusing in Fenton and Fenton-like reactions. These properties allowed GA-Fe@HMDN-PEI-PEG for precise medicine with a high utilization rate and common side effects.

Construction of K and Tb Co-doped MnO2 nanoparticles for enhanced oxidation and detoxication of organic dye waste.

Developing low-cost and efficient materials for dye pollutant removal under mild condition remains a great challenge. Here K+ and Tb3+ co-doped porous MnO2 (K-Tb-MnO2) nanoparticles with tailored properties including crystal structure, surface area and catalytic activity have been synthesized. Experimental results reveal that K-Tb-MnO2 nanoparticle has higher specific surface area, Mn3+ content and surface oxygen vacancies than pristine MnO2 nanoparticle and single-doped MnO2 materials, showing the uniqueness of dual-doped metal ions. Using methyl blue (MB) as a model pollutant, its removal efficiency by K-Tb-MnO2 nanoparticles within 5 min is 93.6%, which is 18, 8.3, and 2.9 times higher than that of MnO2, K-MnO2, and Tb-MnO2 nanomaterials, respectively. Oxalic acid triggered MnO2 material dissolving assay and FT-IR spectrum suggested that remarkable performance of K-Tb-MnO2 nanoparticle toward MB removal can be attributed to a combined effect of adsorption (16% MB removal) and catalytic degradation (84% MB removal). Moreover, K-Tb-MnO2 nanoparticle mediated MB degradation is demonstrated to be a combination of non-radical oxidation by Mn3+ and radical-participated degradation, with 1O2 as the main species. And the intermediates and pathways of MB degradation were studied by liquid chromatography-mass spectrometry. Importantly, cell viability experiment suggests that the toxicity of MB dye could be efficiently alleviated after the treatment with K-Tb-MnO2 nanoparticle. These results demonstrate the great potential of the novel K-Tb-MnO2 particles to be used as a highly effective nanomaterials to reduce the risk of dye wastes toward the environment and human health.

A biochip based on shell-isolated Au@MnO2 nanoparticle array-enhanced fluorescence effect for simple and sensitive exosome assay.

Exosomes, carrying specific molecular information of their parent cells, have been regarded as a kind of promising noninvasive biomarker for liquid biopsy. Plentiful fluorescence methods have been proposed for exosome assay. However, most of them are dependent on nucleic acid signal amplification strategies, which require complicated sequence design and experimental operation. Herein, a metal-enhanced fluorescence (MEF) biochip based on shell-isolated Au@MnO2 nanoparticle array was designed for simple and sensitive assay of exosomes. The designed method consists of only two parts: signal conversion and MEF amplification. The conversion of exosome signals to DNA signals was realized by means of chain displacement reaction. The subtle conversion effectively averts the effect of steric hindrance on MEF while amplifying the signal easily for the first time. The MEF biochip based on shell-isolated Au@MnO2 nanoparticle array achieves a second signal amplification in a simple way. Profiting from the two signal amplifications, this strategy displays high sensitivity toward exosomes with a detection limit of 4.5 × 103 particles µL-1. Compared with the result without MEF, the sensitivity is enhanced about thirty times. As far as we know, this is the first attempt for exosome assay by using MEF strategy. In addition to the favorable fluorescence enhancement, both shell-isolated Au@MnO2 nanoparticles and Au@MnO2 nanoparticle array show excellent stability in buffer solutions, which is conducive to practical application. Moreover, the proposed method is able to distinguish breast cancer patients from healthy people, showing its potential for exosome-based liquid biopsy.