Metal-organic framework-mediated siRNA delivery and sonodynamic therapy for precisely triggering ferroptosis and augmenting ICD in osteosarcoma.

The complex genomics, immunosuppressive tumor microenvironment (TME), and chemotherapeutic resistance of osteosarcoma (OS) have resulted in limited therapeutic effects in the clinic. Ferroptosis is involved in tumor progression and is regulated mainly by glutathione peroxidase 4 (GPX4). Small interfering RNA (siRNA)-based RNA interference (RNAi) can precisely target any gene. However, achieving effective siRNA delivery is highly challenging. Here, we fabricated a TME-responsive metal-organic framework (MOF)-based biomimetic nanosystem (mFeP@si) with siGPX4 delivery and sonodynamic therapy (SDT) to treat OS by targeting ferroptosis. Under ultrasound (US) irradiation, mFeP@si achieves lysosomal escape via singlet oxygen (1O2)-mediated lysosomal membrane disruption and then accelerates ROS generation and glutathione (GSH) depletion. Meanwhile, siGPX4 silences GPX4 expression by binding to GPX4 mRNA and leads to the accumulation of toxic phospholipid hydroperoxides (PL-OOH), further magnifying the ROS storm and triggering ferroptosis. Notably, synergistic therapy remarkably enhances antitumor effects, improves the immunosuppressive TME by inducing potent immunogenic cell death (ICD), and increases the sensitivity of chemotherapy-resistant OS cells to cisplatin. Overall, this novel nanosystem, which targets ferroptosis by integrating RNAi and SDT, exhibits strong antitumor effects both in vitro and in vivo, providing new insights for treating OS.

Calcium sulfate-Cu2+ delivery system improves 3D-Printed calcium silicate artificial bone to repair large bone defects.

There are still limitations in artificial bone materials used in clinical practice, such as difficulty in repairing large bone defects, the mismatch between the degradation rate and tissue growth, difficulty in vascularization, an inability to address bone defects of various shapes, and risk of infection. To solve these problems, our group designed stereolithography (SLA) 3D-printed calcium silicate artificial bone improved by a calcium sulfate-Cu2+ delivery system. SLA technology endows the scaffold with a three-dimensional tunnel structure to induce cell migration to the center of the bone defect. The calcium sulfate-Cu2+ delivery system was introduced to enhance the osteogenic activity of calcium silicate. Rapid degradation of calcium sulfate (CS) induces early osteogenesis in the three-dimensional tunnel structure. Calcium silicate (CSi) which degrades slowly provides mechanical support and promotes bone formation in bone defect sites for a long time. The gradient degradation of these two components is perfectly matched to the rate of repair in large bone defects. On the other hand, the calcium sulfate delivery system can regularly release Cu2+ in the temporal and spatial dimensions, exerting a long-lasting antimicrobial effect and promoting vascular growth. This powerful 3D-printed calcium silicate artificial bone which has rich osteogenic activity is a promising material for treating large bone defects and has excellent potential for clinical application.

Radial Sponges Facilitate Wound Healing by Promoting Cell Migration and Angiogenesis.

The topographic cues of wound dressings play important roles in regulating cellular behaviors, such as cellular migration and morphology, and are capable of providing a prolonged stimulus for promoting wound healing. However, 3D porous dressings that can guide wound healing from the periphery to the center are poorly studied. Herein, radial sponges with adjustable lamellar spacing and microridge spacing by ice templating are developed to facilitate wound healing. With denser lamellae and microridges, fibroblasts achieve a more orderly arrangement, a larger elongation, and a greater migration rate. Meanwhile, the elongated state enables human umbilical vein endothelial cells to vascularization. The faster healing rate and a higher degree of vascularization based on radial sponges are further demonstrated in full-thickness skin defects in rats. Taken together, radial sponges with the densest lamellae and microridges perform the best in guiding the wound from the periphery to the center of the repair environment. It is believed that the proposed structure here can be combined with various biochemical factors to provide dressings with functions.

A Composite of Cubic Calcium-Magnesium Sulfate and Bioglass for Bone Repair.

Calcium sulfate (CS) bone cement has been shown to have good biocompatibility and can be used as a bone filler for repairing bone defects. However, its clinical application is limited due to its low compressive strength and weak bone repair activity. To this end, in this study, cubic crystalline magnesium-doped calcium sulfate (MgCS) was prepared and mixed with 45S5 bioglass (BG) to form a composite bone cement (MgCS/BG). The results show that cubic crystal calcium sulfate helps to increase the compressive strength of the composite bone cement to more than 60 MPa. More importantly, the obtained magnesium-doped composite bone cement can promote the adhesion and differentiation of mesenchymal stem cells and has good bioactivity. Through a skull defect model, it was found that MgCS/BG can significantly enhance bone defect repair and new bone formation. This new composite MgCS/BG is very promising for future translation into clinical applications.