A pH/GSH/Glucose Responsive Nanozyme for Tumor Cascade Amplified Starvation and Chemodynamic Theranostics.

Nanozymes have brought enormous opportunities for disease theranostics. Here, a self-enhanced catalytic nanocrystal based on a bismuth-manganese core-shell nanoflower containing glucose oxide (GOx), termed BDS-GOx@MnOx, was designed for 4T1 tumor theranostics in vitro and in vivo. The BDS-GOx@MnOx nanozymes enable enhanced starvation treatment (ST) and chemotherapy (CDT) with high efficacy and exhibit sensitive tumor microenvironment (TME) responsive character for tumor therapy as well as for tumor-enhanced computer tomography (CT) and magnetic resonance (MR) diagnostic imaging. The characters and mechanism of the BDS-GOx@MnOx nanozymes have also been systematically studied and revealed.

Copper Doped Carbon Dots for Addressing Bacterial Biofilm Formation, Wound Infection, and Tooth Staining.

Oral infectious diseases and tooth staining, the main challenges of dental healthcare, are inextricably linked to microbial colonization and the formation of pathogenic biofilms. However, dentistry has so far still lacked simple, safe, and universal prophylactic options and therapy. Here, we report copper-doped carbon dots (Cu-CDs) that display enhanced catalytic (catalase-like, peroxidase-like) activity in the oral environment for inhibiting initial bacteria (Streptococcus mutans) adhesion and for subsequent biofilm eradication without impacting the surrounding oral tissues via oxygen (O2) and reactive oxygen species (ROS) generation. Especially, Cu-CDs exhibit strong affinity for lipopolysaccharides (LPS) and peptidoglycans (PGN), thus conferring them with excellent antibacterial ability against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli), such that they can prevent wound purulent infection and promoting rapid wound healing. Additionally, the Cu-CDs/H2O2 system shows a better performance in tooth whitening, compared with results obtained with other alternatives, e.g., CDs and clinically used H2O2, particularly its negligible enamel and dentin destruction. It is anticipated that the biocompatible Cu-CDs presented in this work are a promising nano-mouthwash for eliminating oral pathogenic biofilms, prompting wound healing as well as tooth whitening, highlighting their significance in oral health management.

Biocompatible tellurium nanoneedles with long-term stable antibacterial activity for accelerated wound healing.

Tellurium (Te) nanomaterials (NMs) have emerged as a new antibacterial candidate to respond to the complex global health challenge of bacterial resistance. Herein, Te nanoneedles (NNs) that act both chemically and physically on bacteria are synthesized by a facile method using Na2TeO3, urea and glucose. It is found that the prepared Te NNs have a strong affinity to the cell membrane of bacteria and subsequently promote the generation of reactive oxygen species (ROS) in bacteria, resulting in an excellent antibacterial effect toward Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). What's more, this needle-like morphology also can physically damage the bacterial cell membranes. The Te NNs per se are inert in mammalian cells to produce ROS at a proper concentration, indicating considerable biocompatibility of this material. As a proof-of-concept, the antibacterial Te NNs were used as an anti-inflammatory reagent for promoting bacteria-infected wound healing in vivo, during which Te NNs caused no evident side effects to major organs in mice. Additionally, the antibacterial activity is maintained in the presence of surface oxidation of Te NNs after long-term dispersion in phosphate buffered saline solution. The needle-like Te NMs with long-term antibacterial stability and good biocompatibility have great potential for the treatment of associated infectious diseases.

Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells.

Traditional medication is not satisfied in rheumatoid arthritis (RA) therapy due to its long-term side effects and failure in cartilage repair. Nanomodification of mesenchymal stem cells (MSCs) holds promise for lifting such hurdles but delivering therapeutic nanomaterials (NPs) into MSCs remains challenging in this new strategy. Here, we show that CuS@MnO2 NPs functionalized with a short phage-selected MSC-targeting peptide enabled the NPs to be uptaken by MSCs. The resultant NP-modified MSCs, further loaded with metformin, significantly improved stem cell therapy of RA. Specifically, the NP-modified MSCs survived the RA-associated oxidized stress through regulating the stress by the superoxide dismutase (SOD)- and catalase (CAT)-like activity of the NPs. They also exhibited an increased capability of cell migration, anti-inflammation, and chondrogenesis due to the nanomodification, thereby effectively inhibiting synovial inflammation and reducing cartilage erosion to relieve RA symptoms in two rat models 28 days post intravenous injection. Our peptide-promoted NP-modified MSCs may be used to enhance therapeutic effects in treating not only RA but also other degenerative and inflammatory diseases.

Immunotherapy for Tumor Metastasis by Artificial Antigen-Presenting Cells via Targeted Microenvironment Regulation and T-Cell Activation.

Effective expansion of T-cells without ex vivo stimulation and maintenance of their antitumor functions in the complex tumor microenvironment (TME) are still daunting challenges in T-cell-based immunotherapy. Here, we developed biomimetic artificial antigen-presenting cells (aAPCs), ultrathin MnOx nanoparticles (NPs) functionalized with T-cell activators (anti-CD3/CD28 mAbs, CD), and tumor cell membranes (CMs) for enhanced lung metastasis immunotherapy. The aAPCs, termed CD-MnOx@CM, not only efficiently enhanced the expansion and activation of intratumoral CD8+ cytotoxic T-cells and dendritic cells after homing to homotypic metastatic tumors but also regulated the TME to facilitate T-cell survival through catalyzing the decomposition of intratumoral H2O2 into O2. Consequently, the aAPCs significantly inhibited the development of lung metastatic nodules and extended the survival of a B16-F10 melanoma metastasis model, while minimizing adverse events. Our work represents a new biomaterial strategy of inhibiting tumor metastasis through targeted TME regulation and in situ T-cell-based immunotherapy.

A Honeycomb-Like Bismuth/Manganese Oxide Nanoparticle with Mutual Reinforcement of Internal and External Response for Triple-Negative Breast Cancer Targeted Therapy.

Triple-negative breast cancer (TNBC) exhibits aggressive behavior and high levels of metastasis owing to its complex heterogeneous structure and lack of specific receptors. Here, tumor cell membrane (CM)-coated bismuth/manganese oxide nanoparticles (NPs) with high indocyanine green (ICG) payload up to 50.6 wt% (mBMNI NPs) for targeted TNBC therapy are constructed. The extra-high drug load Bi@Bi2 O3 @MnOx NPs (honey-comb like structure) are formed by Kirkendall effect and electrostatic attraction. After modified with CM, they can home into tumor sites precisely, where they respond to internal overexpressed glutathione (GSH), releasing Mn2+ for chemodynamic therapy (CDT) with GSH depletion, while H2 O2 degrades into O2 enabling relief of tumor hypoxia. In response to external near-infrared irradiation, mBMNI NPs intelligently generate vigorous heat and single oxygen (1 O2 ) for photothermal therapy (PTT) and photodynamic therapy (PDT) owing to high load. Importantly, O2 production and GSH consumption during the internal response reinforce external PDT, while the heat generated through PTT during the external response promotes internal CDT. The honeycomb-like structure with high ICG load and mutual reinforcement between internal and external response results in excellent therapeutic effects against TNBC.

Catalytic-Enhanced Lactoferrin-Functionalized Au-Bi2 Se3 Nanodots for Parkinson's Disease Therapy via Reactive Oxygen Attenuation and Mitochondrial Protection.

Overexpression of reactive oxygen species in the substantia nigra pars compacta destroys dopaminergic neurons and accelerates the pathological process of Parkinson's disease (PD). In this study, a new hydrophilic nano-bioconjugate, lactoferrin (Lf)-modified Au-Bi2 Se3 nanodot (ND) for efficient PD therapy is developed. In particular, the Lf-Au-Bi2 Se3 NDs exhibit strong blood-brain barrier (BBB) permeation. The Lf-Au-Bi2 Se3 NDs can also serve as multiple enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and peroxide. These NDs are located close to the mitochondria and thus maintain the mitochondrial membrane potential as well as control the cellular ROS level. In vivo results further demonstrate that the NDs can improve the memory and mobility of PD mice; permeation of the BBB, protection of mitochondria, and suppression of dopaminergic neuron loss in the substantia nigra pars compacta are also observed. It is anticipated that these new Lf-Au-Bi2 Se3 NDs with excellent biocompatibility, multienzyme functionality, and BBB permeability will open new opportunities for PD therapy.

AgBiS2 nanoparticles with synergistic photodynamic and bioimaging properties for enhanced malignant tumor phototherapy.

Bismuth (Bi)-based nanoagents for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) are attracting attention and are highly desired for malignant tumor diagnosis and treatment, but producing these materials is still a challenge. Here, we designed theranostic nanoparticles (NPs) based on AgBiS2 for computed tomography (CT) imaging and phototherapy of malignant tumors. These AgBiS2 NPs could effectively convert light into heat (with a high photothermal conversion efficiency of 36.51%) and significantly increase the generation of intracellular reactive oxygen species (ROS) under near infrared (NIR) laser irradiation. Remarkably, the combined PTT/PDT successfully inhibited the growth of a highly malignant osteosarcoma in vivo. In addition, AgBiS2 NPs exhibited an enhanced CT contrast ability for tumor imaging and killed clinically derived Staphylococcus aureus (S. aureus) to prevent infection. In conclusion the ability of AgBiS2 NPs to be used in phototherapy and CT imaging and their antibacterial abilities indicate that they are promising candidates for malignant tumor theranostics.

Visualizing Dynamic Performance of Lipid Droplets in a Parkinson's Disease Model via a Smart Photostable Aggregation-Induced Emission Probe.

Parkinson's disease (PD) is a complex neurodegenerative disease affected by diverse factors, and lipid droplets (LDs) are increasingly recognized as major players in PD because of their relevance to neuron activity. However, long-term dynamic changes of LDs and their relative activity remain unclear. Here, an aggregation-induced emission (AIE) probe named 2-DPAN was prepared and employed to visualize dynamic processes of LDs in a 6-hydroxydopamine model of PD for the first time, and LDs' accumulation-peak/plateau-decrease were confirmed. We further found a close relationship between LDs and variation in mitochondrial activity. Strikingly, the progression of cell death was accelerated by lipase, whereas pre-stimulation of LDs by unsaturated fatty acid-oleic acid decreased the death process by inhibiting excessive reactive oxygen species (ROS) and fatty acid production, thereby protecting mitochondria. The utilization of 2-DPAN demonstrates the importance of LDs in neuronal homeostasis, and effective tuning of LDs may prevent or inhibit PD progression.

[Efficacy assessment of treating post-stroke shoulder-hand syndrome patients of yin deficiency yang hyperactivity with blood stasis stagnation collaterals syndrome by yishen tongluo decoction].

OBJECTIVE: To assess the efficacy of Yishen Jiejing Decoction (YJD) in treating poststroke shoulder-hand syndrome (SHS) patients of yin deficiency yang hyperactivity with blood stasis stagnation collaterals syndrome. METHODS: Totally 60 SHS patients of yin deficiency yang hyperactivity with blood stasis stagnation collaterals syndrome were randomly assigned to two groups, the treatment group and the control group, 30 cases in each group. Conventional rehabilitation training and therapeutics were applied in all patients. Besides, patients in the treatment group took 50 mL YJD, twice a day. One month without interruption consisted of one course of treatment. The curative effects of each group were evaluated respectively before treatment and at one month after treatment. The neurologic impairment, TCM syndrome, and the improvement of upper limbs movement were assessed by the neurologic impairment integral, scoring for TCM syndrome diagnostics, Fugl-Meyer Assessment (U-FMA). Adverse reactions were observed at the same time. RESULTS: The effective rate of stroke was 86.67% and the effective rate of SHS was 90.00% in the treatment group, higher than those of the control group (P < 0.05). Both groups got improvement in neurologic impairment, stroke induced blood stasis syndrome, yin deficiency yang hyperactivity syndrome, and the improvement of upper limbs movement after treatment (all P < 0.05). Besides, all the improvement was obviously superior in the treatment group (P < 0. 05). No adverse reaction occurred during the course of treatment. CONCLUSION: The curative effect of YJD combined with conventional rehabilitation training was confirmative and superior to the control group.