Zhijun Hu

Osteochondral defects pose a significant clinical challenge due to their limited capacity for self‐repair. Although arthroplasty is commonly performed, serious complications remain a major concern. In this study, a novel ultrasmall Prussian blue (USPB) nanozyme‐functionalized 3D‐printed gradient antioxidant scaffold was fabricated. Osteogenic and antisenescence hydrogels were incorporated into the subchondral and cartilage regions, respectively. The scaffold's performance, including biocompatibility, effects on cellular senescence, osteogenic differentiation, and underlying mechanisms, was evaluated through a series of in vitro and in vivo assays. The composite scaffold effectively scavenged reactive oxygen species (ROS) and enhanced the endogenous antioxidant defense system in both C28 chondrocytes and rat bone marrow stem cells (rBMSCs). Mechanistically, the cartilage region of the scaffold maintained cellular homeostasis by upregulating GPX4 expression, inhibiting ferroptosis, and bolstering antisenescence activity. In the subchondral region, the scaffold promoted osteogenic differentiation and mineralization of rBMSCs by activating the PI3K‐AKT signaling pathway. This study presents a biomimetic scaffold that demonstrates significant potential for osteochondral repair while systematically elucidating the mechanisms governing cellular homeostasis. These findings provide a foundation for the development of next‐generation multifunctional tissue engineering platforms.

As a central driver of intervertebral disc degeneration (IVDD), oxidative stress mediates pathological changes by promoting extracellular matrix (ECM) breakdown, thereby accelerating the degenerative process. To target this pathological cascade, trimetallic nanoparticles (TriNPs) are designed and developed to modulate the oxidative microenvironment of intervertebral discs and restore ECM homeostasis through reactive oxygen species (ROS) scavenging. In vitro studies demonstrate that TriNPs provide significant cytoprotection against H ₂ O ₂ ‐induced oxidative damage in nucleus pulposus (NP) cells through efficient ROS elimination. For translational applications, TriNPs are encapsulated within an injectable hydrogel (termed TOH) to evaluate their therapeutic potential in a rat IVDD model. In vivo studies encompassing both radiographic and histomorphometric analyses reveal that TOH administration significantly improves the Disc Height Index (DHI) and T2‐weighted Magnetic Resonance Imaging (MRI) grading, while also reducing histological scores. Collectively, these results indicate that TOH may serve as an innovative therapeutic approach to modulate disc microenvironment and attenuate IVDD progression.

Post‐surgical recurrence and extensive bone defects pose significant challenges during osteosarcoma treatment. These issues can be addressed using a novel strategy that promotes bone repair after removing residual tumors. Therefore, a 3D‐printed porous polylactic acid (PLA) scaffold (PH‐GBS@CCP) filled with hydrogel and surface‐modified with nano‐hydroxyapatite (nHA) is designed. The hydrogel, composed of gelatin modified with methacrylic anhydride (GelMA), sodium alginate (SA), and borax, contains Cu–Cys–PEG nanoparticles (CCP) modified with cRGD_fk‐PEG_2K‐DSPE. It is injected into the PLA scaffold and crosslinked under UV. This hydrogel acts as a buffer medium between scaffold and bone, reducing cell abrasion, and as a carrier for the responsive release of tumor‐targeting CCP. The scaffold provides the support and microenvironment required for bone repair. In early treatment, the acidic tumor microenvironment promotes hydrogel disintegration and CCP release, depleting glutathione and converting Cu²⁺ to Cu⁺ for the Fenton‐like reaction. This generates reactive oxygen species, strengthening the proptosis effect, and killing the tumor. In later treatment, after tumor elimination, normalized pH and slow CCP release, along with scaffold nHA, promote osteogenic differentiation, providing a sustained osteogenic effect. Overall, the multifunctional composite scaffold achieved the sequential management of post‐surgical osteosarcoma through early tumor‐killing and later osteogenic effects.

Clusterzymes are synthetic enzymes exhibiting substantial catalytic activity and selectivity, which are uniquely driven by single-atom constructs. A dramatic increase in antioxidant capacity, 158 times more than natural trolox, is noted when single-atom copper is incorporated into gold-based clusterzymes to form Au₂₄Cu₁. Considering the inflammatory and mildly acidic microenvironment characteristic of osteoarthritis (OA), pH-dependent dendritic mesoporous silica nanoparticles (DMSNs) coupled with PEG have been employed as a delivery system for the spatial-temporal release of clusterzymes within active articular regions, thereby enhancing the duration of effectiveness. Nonetheless, achieving high therapeutic efficacy remains a significant challenge. Herein, we describe the construction of a Clusterzymes-DMSNs-PEG complex (CDP) which remarkably diminishes reactive oxygen species (ROS) and stabilizes the chondroprotective protein YAP by inhibiting the Hippo pathway. In the rabbit ACLT (anterior cruciate ligament transection) model, the CDP complex demonstrated inhibition of matrix metalloproteinase activity, preservation of type II collagen and aggregation protein secretion, thus prolonging the clusterzymes' protective influence on joint cartilage structure. Our research underscores the efficacy of the CDP complex in ROS-scavenging, enabled by the release of clusterzymes in response to an inflammatory and slightly acidic environment, leading to the obstruction of the Hippo pathway and downstream NF-κB signaling pathway. This study illuminates the design, composition, and use of DMSNs and clusterzymes in biomedicine, thus charting a promising course for the development of novel therapeutic strategies in alleviating OA.

Background: The incidence of osteochondral defects caused by trauma, arthritis or tumours is increasing annually, but progress has not been made in terms of treatment methods. Due to the heterogeneous structure and biological characteristics of cartilage and subchondral bone, the integration of osteochondral repair is still a challenge. Results: In the present study, a novel bilayer hydrogel scaffold was designed based on anatomical characteristics to imitate superficial cartilage and subchondral bone. The scaffold showed favourable biocompatibility, and the addition of an antioxidant nanozyme (LiMn₂O₄) promoted reactive oxygen species (ROS) scavenging by upregulating antioxidant proteins. The cartilage layer effectively protects against chondrocyte degradation in the inflammatory microenvironment. Subchondral bionic hydrogel scaffolds promote osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) by regulating the AMPK pathway in vitro. Finally, an in vivo rat preclinical osteochondral defect model confirmed that the bilayer hydrogel scaffold efficiently promoted cartilage and subchondral bone regeneration. Conclusions: In general, our biomimetic hydrogel scaffold with the ability to regulate the inflammatory microenvironment can effectively repair osteochondral defects. This strategy provides a promising method for regenerating tissues with heterogeneous structures and biological characteristics. Graphical

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-κβ 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.

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 cRGD_fk-PEG_2k-DSPE, T-HCN@CuMS was prepared and endowed with improved dispersibility and α_vβ₃ 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.