Abstract Glioblastoma (GBM) suffers from a poor prognosis due to its highly invasive nature, limited drug delivery across the blood–brain barrier (BBB), and intrinsic radioresistance. Although radiotherapy (RT) can perturb copper homeostasis and induce cuproptosis, the extent of copper accumulation is typically insufficient for effective tumor suppression. Herein, we develop a multifunctional composite nanoplatform, Mn 3 O 4 @PDA/Cu 2 O–Angiopep-2 (MPCA), that integrates BBB penetration, radiosensitization, and copper-mediated cytotoxicity. Angiopep-2 facilitates LRP1-mediated BBB transcytosis and glioma targeting, x-ray diffraction and x-ray photoelectron spectroscopy confirmed the coexistence of crystalline Mn 3 O 4 and Cu 2 O phases and the predominantly Cu(I) state of copper in the composite nanoplatform. Following cellular internalization, MPCA functions as both a copper reservoir and a reactive oxygen species (ROS) amplifier. The Cu 2 O component enables sustained copper release, whereas Mn 3 O 4 enhances irradiation-induced oxidative stress. Under mildly acidic conditions, MPCA exhibits increased copper release, while x-ray irradiation amplifies ROS generation, with the strongest oxidative response observed under combined acidic and irradiation conditions. Mechanistically, MPCA combined with RT increases intracellular copper accumulation, disrupts copper homeostasis, and exacerbates mitochondrial oxidative stress, thereby inducing cuproptosis-associated mitochondrial dysfunction. These effects markedly enhance the radiosensitivity of GBM and inhibit orthotopic tumor growth. Overall, this study presents an Angiopep-2-functionalized Cu–Mn oxide composite nanoplatform that combines BBB targeting with copper-mediated radiosensitization, providing a promising strategy for GBM RT.
Abstract Most existing wound dressings provide only passive hemostasis and protection, and lack robust bio-interactions, active coagulation capabilities, or pro-healing functions, often leading to prolonged bleeding, delayed repair or recurrent bleeding. This paper describes a multifunctional spongy dressing fabricated via thermo-aided citrate cross-linking of pullulan, incorporating tissue factor (TF, a potent physiological coagulation initiator) and collagen. The composite sponge featured an interconnected hierarchical porous structure (porosity >80%) for high blood absorption, along with favorable mechanical strength and shape-recovery property. Functional analysis demonstrated that TF encapsulation accelerated in vitro whole blood coagulation and reduced bleeding time and blood loss by ∼73.9% and ∼77.7% in a rat liver injury model, while collagen encapsulation promoted full-thickness skin wound healing. These effects stem from three synergistic mechanisms: pullulan’s porous structure and large surface area enabling ample interactions with blood or the wound bed, TF amplifying extrinsic coagulation, and collagen inducing clot formation and tissue repair. Additionally, the sponge comprising multiple bio-derived components exhibited good biocompatibility. These findings establish the TF-incorporated cross-linked pullulan/collagen sponge as a highly promising platform for addressing heavy bleeding and orchestrating subsequent wound healing.
The pronounced heterogeneity of the pathological microenvironment in musculoskeletal disorders poses significant challenges to the spatiotemporal regulation capabilities of conventional therapeutic strategies. Stimuli-responsive hydrogels have exhibited immense potential for the treatment of musculoskeletal disorders owing to their excellent intelligent response characteristics and versatile design. This review systematically summarizes the major response mechanisms of stimuli-responsive hydrogels and analyzes the characteristics of their structural and functional design. It further focuses on recent advances of their applications in typical musculoskeletal disorders, including degenerative diseases such as osteoarthritis (OA); autoimmune diseases such as rheumatoid arthritis (RA); traumatic injuries such as fractures and cartilage injury; infectious diseases such as infected bone defects; metabolism-related bone disorders such as diabetic bone injury and hyperlipidemia bone injury; as well as soft tissue complications such as tendon adhesion and rotator cuff injury. Finally, this review proposes a design concept for multimodal stimuli-responsive hydrogels and discusses the key challenges in their clinical translation. We hope this review will serve as a reference for promoting the treatment of musculoskeletal disorders from passive repair to active regulation.
High-entropy alloys (HEAs) have emerged as promising candidates for cardiovascular implants due to their adjustable phase structure and excellent mechanical reliability. However, it remains challenging to achieve both mechanical resilience and biological endothelialization simultaneously.
This study engineered CuCoZrNbAl HEAs by adjusting the Al content and thermal processing to explore the relationship between composition, microstructure, nanomechanical, and biological properties for stent-graft applications. Increasing the Al content alongside prolonged heat treatment facilitated the formation of a refined dual-phase microstructure comprising a face-centered cubic matrix and body-centered cubic ZrAl intermetallic domains.
Among all tested alloys, the optimized CCZN(Al1.0)-H60 alloy exhibited favorable nanomechanical properties, achieving a contact hardness of 11.2 GPa, a Young's modulus of 186.20 GPa, and a remarkably high H/E ratio of 0.060, alongside a reduced indentation depth of 6.51 nm and reduced hysteretic dissipated energy of 455.52×10-18 J. Furthermore, this alloy displayed enhanced electrochemical stability with a low corrosion current density of 1.53 μA/cm2. Surface homogenization and Al-rich phase stabilization significantly enhanced endothelial cell attachments, supporting cell viability exceeding 100% and preserved migration capacity. The hemocompatibility test indicated a hemolysis rate below 2%, suggesting non-hemolytic behavior.
These findings demonstrate that Al-driven phase engineering effectively strengthens local deformation resistance and corrosion stability while supporting endothelial cell growth, highlighting CuCoZrNbAl HEAs as potential candidates for further development of stent-grafts.
The total flavonoids of Rhizoma Drynariae (TFRD) are traditionally used to repair bone defects. Magnesium phosphate cement (MPC) features high early strength, fast setting, good biocompatibility and osteoconductivity. Cobalt-doped hydroxyapatite (Co-HA) exerts a significant role in guiding the osteogenic and angiogenic differentiation of bone marrow stromal cells (BMSCs). We herein hypothesize that incorporating TFRD into MPC/Co-HA yields composite scaffolds with sustained drug release and self-setting capacity, capable of inducing osteogenesis in vitro and accelerating bone repair in vivo. Accordingly, MPC/Co-HA/TFRD composites were fabricated with various TFRD loadings. The results showed that TFRD was uniformly dispersed in the MPC/Co-HA matrix. It cleared that MPC/Co-HA/TFRD composites exhibited characteristic chemical constitution of MPC，Co-HA and TFRD, with no new phases formed. In addition, the weight loss ratio of the MPC/Co-HA/TFRD composites increased with increasing TFRD content, and the pH of the composite soaking solution remained within a range suitable for the human physiological environment throughout the immersion period. Drug release studies demonstrated that the MPC/Co-HA/TFRD composites exhibited an initial burst release within 48 h, followed by a sustained slow-release pattern. In vitro cellular experiments verified that the 5 wt% TFRD-loaded MPC/Co-HA/TFRD5 composite remarkably enhanced BMSCs proliferation. The incorporation of TFRD into MPC/Co-HA enhanced alkaline phosphatase (ALP) activity and accelerated calcium nodule formation, indicating that the composites effectively induced osteogenic differentiation of BMSCs. The introduction of TFRD into MPC/Co-HA upregulated the expression of osteogenic-related proteins (IBSP, Runx2, and Osterix) and angiogenesis-related proteins (OPN, HIF-1α, and HO-1) in BMSCs. In vivo results revealed that the MPC/Co-HA/TFRD5 scaffold implanted into femoral condyle bone defects in New Zealand white rabbits significantly accelerated bone regeneration 8 weeks after surgery and exhibited favorable osteoconductivity. Hence, the MPC/Co-HA/TFRD composite represents a promising candidate scaffold for bone tissue regeneration applications.
