Copper-Loaded Nanoheterojunction Enables Superb Orthotopic Osteosarcoma Therapy via Oxidative Stress and Cell Cuproptosis.

Catalytic tumor therapy based on two-dimensional (2D) nanomaterials is a burgeoning and promising tumor therapeutic modality. However, the inefficient utilization and conversion of exogenous stimulation, single catalytic modality, and unsatisfactory therapeutic efficiency in the tumor microenvironment (TME) have seriously restricted their further application in tumor therapy. Herein, the heterogeneous carbon nitride-based nanoagent named T-HCN@CuMS was successfully developed, which dramatically improved the efficiency of the tumor therapeutic modality. Benefiting from the donor-acceptor (triazine-heptazine) structure within the heterogeneous carbon nitride nanosheets (HCN) and the construction of interplanar heterostructure with copper loaded metallic molybdenum bisulfide nanosheets (CuMS), T-HCN@CuMS presented a favorable photo-induced catalytic property to generate abundant reactive oxygen species (ROS) under near-infrared (NIR) light irradiation. Besides, the choice of CuMS simultaneously enabled this nanoagent to efficiently catalyze the Fenton-like reaction and trigger cell cuproptosis, a recently recognized regulated cell death mode characterized by imbalanced intracellular copper homeostasis and aggregation of lipoylated mitochondrial proteins. Moreover, upon surface modification with cRGDfk-PEG2k-DSPE, T-HCN@CuMS was prepared and endowed with improved dispersibility and αvß3 integrins targeting ability. In general, through the rational design, T-HCN@CuMS was facilely prepared and had achieved satisfactory antitumor and antimetastasis outcomes both in vitro and in a high-metastatic orthotopic osteosarcoma model. This strategy could offer an idea to treat malignant diseases based on 2D nanomaterials.

Osteoimmunity-Regulating Biomimetically Hierarchical Scaffold for Augmented Bone Regeneration.

Engineering a proper immune response following biomaterial implantation is essential to bone tissue regeneration. Herein, a biomimetically hierarchical scaffold composed of deferoxamine@poly(ε-caprolactone) nanoparticles (DFO@PCL NPs), manganese carbonyl (MnCO) nanosheets, gelatin methacryloyl hydrogel, and a polylactide/hydroxyapatite (HA) matrix is fabricated to augment bone repair by facilitating the balance of the immune system and bone metabolism. First, a 3D printed stiff scaffold with a well-organized gradient structure mimics the cortical and cancellous bone tissues; meanwhile, an inside infusion of a soft hydrogel further endows the scaffold with characteristics of the extracellular matrix. A Fenton-like reaction between MnCO and endogenous hydrogen peroxide generated at the implant-tissue site triggers continuous release of carbon monoxide and Mn2+ , thus significantly lessening inflammatory response by upregulating the M2 phenotype of macrophages, which also secretes vascular endothelial growth factor to induce vascular formation. Through activating the hypoxia-inducible factor-1α pathway, Mn2+ and DFO@PCL NP further promote angiogenesis. Moreover, DFO inhibits osteoclast differentiation and synergistically collaborates with the osteoinductive activity of HA. Based on amounts of data in vitro and in vivo, strong immunomodulatory, intensive angiogenic, weak osteoclastogenic, and superior osteogenic abilities of such an osteoimmunity-regulating scaffold present a profound effect on improving bone regeneration, which puts forward a worthy base and positive enlightenment for large-scale bone defect repair.

Clinical trials of stem cell-based therapies for pediatric diseases: a comprehensive analysis of trials registered on ClinicalTrials.gov and the ICTRP portal site.

BACKGROUND: Research on clinical trials that employ stem cells to treat children's diseases is limited. The clinical trial registry database provides a unique window to us to get known about clinical trial researches with different statuses. However, few studies aimed to perform a comprehensive and thorough analysis of those registered trials in the aforementioned field based on ClinicalTrials.gov and the ICTRP portal site. METHODS: Our study covered the clinical researches about stem cell therapy enrolling subjects aged under 18 years old registered on ClinicalTrials.gov and WHO ICTRP before May 18, 2021. A cross-sectional study was implemented to comprehensively describe and analyze the included trials that met the criteria. Results were available on ClinicalTrials.gov, and publications related to the included trials were identified. All analyses were performed utilizing the SPSS 25.0 software. RESULTS: Eventually, 202 clinical trials were included and evaluated. The participant number of trials tended to be small; 71.3% were enrolled < 50. And 93.5% of the subjects were without gender restrictions. Till May 2020, 112 trials had been preliminary completed, of which only 39 trials had published papers or uploaded results. Most (73.6%) of 186 interventional trials were in phase 1 and phase 2, where 131 (70.4%) trials were conducted without masking, and 26.3% trials were randomized; 55.4% trials were performed single group assignment. Of 16 observational trials, case-only/series took up 37.5%. Hematopoietic stem cells (37.1%) and mesenchymal stem cells (36.1%) were mostly employed, while umbilical cord blood (UCB)-derived cells (24.3%) and bone marrow (BM)-derived cells (20.8%) were the major sources. CONCLUSIONS: This study provided an overall picture of utilizing stem cells for treatment and management of childhood diseases. Since clinical trials in this area are insufficient in quantity and quality, there is an urgent need of larger, better-designed trials. Increased investment in clinical research of stem cell treatment products should be carried out to achieve the transformation of results as soon as possible. Moreover, it is important to optimize the management of the registration platform and shorten the time it takes for research results to be published.

Biologically Responsive Plasmonic Assemblies for Second Near-Infrared Window Photoacoustic Imaging-Guided Concurrent Chemo-Immunotherapy.

We developed dual biologically responsive nanogapped gold nanoparticle vesicles loaded with immune inhibitor and carrying an anticancer polymeric prodrug for synergistic concurrent chemo-immunotherapy against primary and metastatic tumors, along with guided cargo release by photoacoustic (PA) imaging in the second near-infrared (NIR-II) window. The responsive vesicle was prepared by self-assembly of nanogapped gold nanoparticles (AuNNPs) grafted with poly(ethylene glycol) (PEG) and dual pH/GSH-responsive polyprodug poly(SN38-co-4-vinylpyridine) (termed AuNNP@PEG/PSN38VP), showing intense PA signal in the NIR-II window. The effect of the rigidity of hydrophobic polymer PSN38VP on the assembled structures and the formation mechanism of AuNNP@SN38 Ve were elucidated by computational simulations. The immune inhibitor BLZ-945 was encapsulated into the vesicles, resulting in pH-responsive release of BLZ-945 for targeted immunotherapy, followed by the dissociation of the vesicles into single AuNNP@PEG/PSN38VP. The hydrophilic AuNNP@PEG/PSN38VP nanoparticles could penetrate deep into the tumor tissues and release the anticancer drug SN38 under the reductive environment. A PA signal in the NIR-II window in the deep tumor region was obtained. The BLZ-945-loaded vesicle enabled enhanced PA imaging-guided concurrent chemo-immunotherapy efficacy, inhibiting the growth of both primary tumors and metastatic tumors.

Gold Nanoparticle-Decorated g-C3N4 Nanosheets for Controlled Generation of Reactive Oxygen Species upon 670 nm Laser Illumination.

Conventional photosensitizer-based photodynamic therapy is triggered by UV-light irradiation and depends on oxygen. However, it is hard to be applied to the deep and hypoxic tumor. To address this issue, we reported a new kind of g-C3N4 nanosheet decorated with gold nanoparticles (AuNPs), which could generate a high amount of reactive oxygen species (ROS) under a 670 nm laser irradiation in an oxygen-free environment. This synthesized semiconductor-metal heterojunction served as a superior photodynamic agent, showing prominent cancer cell-killing and tumor growth-suppressing effects in the presence of a 670 nm light and g-C3N4-AuNP composites, and its excellent ROS generation property was also validated by further bactericidal experiment.

Polyphenol-Inspired Facile Construction of Smart Assemblies for ATP- and pH-Responsive Tumor MR/Optical Imaging and Photothermal Therapy.

Smart assemblies have attracted increased interest in various areas, especially in developing novel stimuli-responsive theranostics. Herein, commercially available, natural tannic acid (TA) and iron oxide nanoparticles (Fe3 O4 NPs) are utilized as models to construct smart magnetic assemblies based on polyphenol-inspired NPs-phenolic self-assembly between NPs and TA. Interestingly, the magnetic assemblies can be specially disassembled by adenosine triphosphate, which shows a stronger affinity to Fe3 O4 NPs than that of TA and partly replaces the surface coordinated TA. The disassembly can further be facilitated by the acidic environment hence causing the remarkable change of the transverse relaxivity and potent "turn-on" of fluorescence (FL) signals. Therefore, the assemblies for specific and sensitive tumor magnetic resonance and FL dual-modal imaging and photothermal therapy after intravenous injection of the assemblies are successfully employed. This work not only provides understandings on the self-assembly between NPs and polyphenols, but also will open new insights for facilely constructing versatile assemblies and extending their biomedical applications.