Multifunctional nanomaterials via cell cuproptosis and oxidative stress for treating osteosarcoma and OS-induced bone destruction.

Reactive Oxygen Species (ROS) refers to a highly reactive class of oxidizing species that have the potential to induce cellular apoptosis and necrosis. Cuproptosis, a type of cell death, is primarily associated with the effects of copper ions. However, the specific relationship between ROS, cuproptosis, and osteosarcoma (OS) remains relatively unexplored. Additionally, there is limited research on the use of cuproptosis in conjunction with oxidative stress for treating OS and inhibiting tumor-induced bone destruction. To address these gaps, a novel treatment approach has been developed for OS and neoplastic bone destruction. This approach involves the utilization of glutathione (GSH) and pH-responsive organic-inorganic mesoporous silica nanoparticles@Cu2S@oxidized Dextran (short for MCD). The MCD material demonstrates excellent cytocompatibility, osteogenesis, tumor suppression, and the ability to inhibit osteoclast formation. The specific mechanism of action involves the mitochondria of the MCD material inhibiting key proteins in the tricarboxylic acid (TCA) cycle. Simultaneously, the generation of ROS promotes this inhibition and leads to alterations in cellular energy metabolism. Moreover, the MCD biomaterial exhibits promising mild-temperature photothermal therapy in the second near-infrared (NIR-II) range, effectively mitigating tumor growth and OS-induced bone destruction in vivo.

Selective Autophagy Receptor NBR1 Retards Nucleus Pulposus Cell Senescence by Directing the Clearance of SRBD1.

Intervertebral disc degeneration (IDD) is a prevalent degenerative disorder that closely linked to aging. Numerous studies have indicated the crucial involvement of autophagy in the development of IDD. However, the non-selective nature of autophagy substrates poses great limitations on the application of autophagy-related medications. This study aims to enhance our comprehension of autophagy in the development of IDD and investigate a novel therapeutic approach from the perspective of selective autophagy receptor NBR1. Proteomics and immunoprecipitation and mass spectrometry analysis, combined with in vivo and in vitro experimental verification were performed. NBR1 is found to be reduced in IDD, and NBR1 retards cellular senescence and senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPCs), primarily through its autophagy-dependent function. Mechanistically, NBR1 knockdown leads to the accumulation of S1 RNA-binding domain-containing protein 1 (SRBD1), which triggers cellular senescence via AKT1/p53 and RB/p16 pathways, and promotes SASP via NF-κß pathway in NPCs. Our findings reveal the function and mechanism of selective autophagy receptor NBR1 in regulating NPCs senescence and degeneration. Targeting NBR1 to facilitate the clearance of detrimental substances holds the potential to provide novel insights for IDD treatment.

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.