Rescuing Nucleus Pulposus Cells from ROS Toxic Microenvironment via Mitochondria-Targeted Carbon Dot-Supported Prussian Blue to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.

Manganese Amplifies Photoinduced ROS in Toluidine Blue Carbon Dots to Boost MRI Guided Chemo/Photodynamic Therapy.

The contrast agents and tumor treatments currently used in clinical practice are far from satisfactory, due to the specificity of the tumor microenvironment (TME). Identification of diagnostic and therapeutic reagents with strong contrast and therapeutic effect remains a great challenge. Herein, a novel carbon dot nanozyme (Mn-CD) is synthesized for the first time using toluidine blue (TB) and manganese as raw materials. As expected, the enhanced magnetic resonance (MR) imaging capability of Mn-CDs is realized in response to the TME (acidity and glutathione), and r1 and r2 relaxation rates are enhanced by 224% and 249%, respectively. In addition, the photostability of Mn-CDs is also improved, and show an efficient singlet oxygen (1 O2 ) yield of 1.68. Moreover, Mn-CDs can also perform high-efficiency peroxidase (POD)-like activity and catalyze hydrogen peroxide to hydroxyl radicals, which is greatly improved under the light condition. The results both in vitro and in vivo demonstrate that the Mn-CDs are able to achieve real-time MR imaging of TME responsiveness through aggregation of the enhanced permeability and retention effect at tumor sites and facilitate light-enhanced chemodynamic and photodynamic combination therapies. This work opens a new perspective in terms of the role of carbon nanomaterials in integrated diagnosis and treatment of diseases.

Rescuing Nucleus Pulposus Cells From Senescence via Dual-Functional Greigite Nanozyme to Alleviate Intervertebral Disc Degeneration.

High levels of reactive oxygen species (ROS) lead to progressive deterioration of mitochondrial function, resulting in tissue degeneration. In this study, ROS accumulation induced nucleus pulposus cells (NPCs) senescence is observed in degenerative human and rat intervertebral disc, suggesting senescence as a new therapeutic target to reverse intervertebral disc degeneration (IVDD). By targeting this, dual-functional greigite nanozyme is successfully constructed, which shows the ability to release abundant polysulfides and presents strong superoxide dismutase and catalase activities, both of which function to scavenge ROS and maintain the tissue at physical redox level. By significantly lowering the ROS level, greigite nanozyme rescues damaged mitochondrial function in IVDD models both in vitro and in vivo, rescues NPCs from senescence and alleviated the inflammatory response. Furthermore, RNA-sequencing reveals ROS-p53-p21 axis is responsible for cellular senescence-induced IVDD. Activation of the axis abolishes greigite nanozyme rescued NPCs senescence phenotype, as well as the alleviated inflammatory response to greigite nanozyme, which confirms the role of ROS-p53-p21 axis in greigite nanozyme's function to reverse IVDD. In conclusion, this study demonstrates that ROS-induced NPCs senescence leads to IVDD and the dual-functional greigite nanozyme holds strong potential to reverse this process, providing a novel strategy for IVDD management.