Metal-ion-mediated lethal pathways offers a highly potent strategy for antibacterial treatments. However, relying on single-pathway mechanisms often fails to overwhelm bacterial antioxidant defenses, reducing antibacterial efficacy. This study designed a heterojunction nanozyme (Cu2O/Fe2O3) that induces ferroptosis-like death and copper-mediated metabolic toxicity exhibiting cuproptosis-like features, achieving highly effective antibacterial treatment. Computational chemistry analysis indicates that the Cu2O/Fe2O3 heterointerface establishes a built-in electric field through spontaneous interfacial electron transfer, thereby enhancing its peroxidase (POD)-like activity. Within the acidic bacterial microenvironment, Cu2O/Fe2O3 catalyzes the generation of large amounts of reactive oxygen species (ROS) and releases metal ions, inducing and amplifying ferroptosis-like death, which disrupts the function of ETC enzymes by attacking iron–sulfur clusters. Concurrently, copper ions disrupt the redox balance by depleting bacillithiol (BSH), indirectly increasing bacterial susceptibility and promoting ferroptosis-like death. Furthermore, the accumulation of copper ions triggers severe metabolic impairments that biochemically resemble the cuproptosis cascade, which disrupts key enzymes of the TCA cycle and impairs the synthesis of electron donors (NADH and FADH2), thereby cutting off the supply of substrates to ETC at the upstream stage. Overall, this study demonstrates that triggering bimetallic ion-mediated metabolic disruptions induces an energy crisis in bacteria, providing a reference for multimodal antibacterial strategies.
Retinal vein occlusion (RVO) causes retinal ischemia, macular edema, and vision loss, yet current anti-vascular endothelial growth factor (anti-VEGF) therapies primarily limit vascular leakage and leave ischemia-driven neuroinflammation insufficiently controlled. Here, we reveal a critical role for microglia-associated NLRP3–IL-18 signaling in amplifying inflammation during early RVO. Bulk retinal RNA sequencing showed broad innate immune activation, whereas single-cell transcriptomic profiling and spatial protein analysis identified prominent inflammasome-related changes in retinal microglia. Constitutive global deletion of Nlrp3 or Il18 attenuated microglial activation and preserved retinal structure and electrophysiological function. To translate this mechanistic insight into a targeted anti-inflammatory strategy, we engineered MG1-functionalized, MCC950-loaded nanoliposomes for microglia-targeted NLRP3 inhibition. MG1 functionalization promoted preferential nanoparticle uptake by activated microglia and suppressed NLRP3–IL-18 signaling more effectively than free MCC950 or non-targeted nanoliposomes. In experimental RVO, a single intravitreal dose administered 6 h after induction alleviated retinal inflammation and edema while preserving retinal electrophysiological responses. These findings establish microglia-associated NLRP3–IL-18 signaling as a therapeutic target in early RVO and support MG1-MCC950 nanoliposomes as a bioactive nanotherapeutic platform for RVO.
Electrospun nanofibers (ESNFs) have become a major focus of modern research given their adaptable architecture, extensive interface, and distinctive physicochemical characteristics, making them appropriate for varied applications such as catalysis and environmental cleanup, drug delivery (DD), tissue engineering (TE), sensing, actuation, and various energy-related technologies. As a result, electrospinning (ES) has emerged as a versatile manufacturing technique, driving intensive efforts to engineer nanofibrous structures specifically for biomedical purposes. Functionalization of ESNFs can be achieved by embedding functional agents or altering surface chemistry to introduce specific functionalities. This review discusses the fabrication methods, optimization techniques, and broad biomedical applications of modified ESNFs, emphasizing their key properties, including biocompatibility, degradability, and safety profile. The article outlines various strategies for creating and modifying ESNFs, followed by a comprehensive analysis of their applications in tissue regeneration, DD, wound repair, antimicrobial therapy, cancer diagnostics and treatment, and biosensing. By critically evaluating recent advances, highlighting future directions, and addressing ongoing challenges about ES, this review underscores the transformative potential of functionalized ESNFs as efficient and adaptable biomaterials for biomedical technologies.
Maintaining appropriate vascular nitric oxide (NO) levels in pulmonary arteries is crucial for the alleviation of pulmonary arterial hypertension (PAH). However, in the injured vascular microenvironment, excessive reactive oxygen species (ROS) deplete NO to generate peroxynitrite, which aggravates the oxidative stress and endothelial dysfunction. Herein, ROS-responsive, zwitterionic nanogels (NGs), containing arginine pendants as NO precursors and encapsulating resveratrol (RSV) as an anti-oxidant, were developed for PAH management via inhalation. Benefiting from their zwitterionic surface that repels mucin adsorption, the inhaled NGs exhibit effective pulmonary mucus penetration and mucosal absorption, enabling robust diffusion to the injured pulmonary arteries. In the oxidative vascular microenvironment, the diselenide crosslinkers within the NGs are cleaved, promoting NGs dissociation and on-demand RSV release. The released RSV scavenges ROS and the arginine pendants are oxidized to generate NO, which cooperate to interrupt the ROS/NO disequilibrium. In a hypoxia/SU5416-induced PAH mouse model, inhaled NGs efficiently alleviate vascular remodeling and reduce pulmonary arterial pressure. This study offers an effective strategy for pulmonary drug delivery, and holds promising potentials for the management of PAH.
Magnetically responsive hydrogels have emerged as promising platforms for remotely modulating HFF-1 fibroblasts behavior through dynamic mechanical stimulation; however, the influence of magnetic nanoparticle spatial organization on magnetic actuation and cell response remains unexplored. Herein, we report the development of chitosan-gelatin magnetic hydrogels with controlled Fe 3 O 4 nanoparticle distribution including homogeneously dispersed, and spatially patterned configurations, as a strategy to engineer localized mechanotransduction and magnetic actuation. The role of nanoparticle organization on the physicochemical, magnetic, and biological properties of the hydrogels has been analyzed. Structural characterization confirmed the successful incorporation of Fe 3 O 4 nanoparticles while preserving their crystalline inverse spinel structure. Morphological and topographical analyses revealed that patterned hydrogels exhibit well-defined nanoparticle-rich and nanoparticle-free regions, generating pronounced microscale heterogeneity throughout the material. The incorporation and spatial confinement of Fe 3 O 4 nanoparticles significantly influenced the hydrogel properties, increasing stiffness, reducing swelling capacity, and enhancing magnetic responsiveness. Notably, patterned hydrogels displayed higher saturation magnetization and magnetic susceptibility than homogeneously dispersed systems, indicating that nanoparticle confinement promotes cooperative magnetic interactions and more efficient magnetic actuation. Biological studies demonstrated excellent cytocompatibility for all hydrogel formulations. While static magnetic stimulation slightly reduced fibroblast proliferation, dynamic magnetic stimulation significantly enhanced cell proliferation, spreading, and cytoskeletal organization, particularly in patterned hydrogels. These effects are attributed to cyclic mechanical cues generated by amplified magnetic-to-mechanical transduction within the patterned magnetic domains. Overall, this study demonstrates that nanoparticle spatial organization is a key design parameter for engineering magnetically responsive hydrogels with tunable magnetic actuation and controllable cellular responses for tissue engineering applications.
