Stroke is a leading global cause of disability and death, with ischemic stroke posing a particularly severe threat. Despite reperfusion therapy, poor outcomes often persist due to oxidative stress, neuroinflammation, and nerve impairment. This study developed an injectable hydrogel based on dual-modified hyaluronic acid for sustained delivery of exosome-cerium oxide nanocomposite (EXO@CeO2), targeting the pathological brain microenvironment after ischemic stroke. In an oxygen-glucose deprivation model, EXO@CeO2 effectively scavenged reactive oxygen species (ROS), reduced ROS-mediated apoptosis, stabilized mitochondrial membrane potential, and modulated inflammation by downregulating pro-inflammatory cytokines (IL-1β, IL-6) and upregulating anti-inflammatory IL-10. It also exhibited pro-angiogenic effects while preserving neuronal structure and function. In a murine photothrombotic stroke model, the hydrogel alleviated cerebral oxidative stress in the acute phase and promoted microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. During recovery, it improved local cerebral blood flow and led to sustained improvements in neurobehavioral function. In summary, this injectable hydrogel enables sustained codelivery of exosomes and cerium oxide, offering a combined therapy integrating antioxidant and exosome-mediated reparative effects for ischemic stroke. Collectively, this dual strategy simultaneously mitigates acute oxidative damage and promotes long-term neurovascular repair.
Yuling Zhao, Wen Zhang, Yue Wang et al.· ACS Applied Materials and In...· 0 citations
Orchestrating tissue regeneration in complex pathologies like post-ischemic stroke requires materials that can precisely regulate multiple signaling pathways. A central challenge is engineering a single platform integrating mechanical, electrical, and biochemical cues to redirect these pathological networks. Here, we present a computation-driven, multimodal hydrogel engineered to function as a programmable regulatory node. The system integrates a computationally screened de novo vasculogenic peptide scaffold and surface-engineered, inflammation-responsive conductive MXene nanosheets. This rational surface engineering solves the critical bottleneck of MXene instability, preserving colloidal stability for over 2 months and maintaining high conductivity (1.2 mS/cm) within the injectable system. In a mouse model of ischemic stroke, this targeted modulation reconstructed the neurovascular unit integrity, suppressed glial scarring, and promoted remyelination and synaptic repair. Crucially, the platform re-established neural electrical signal transmission, leading to the recovery of neural function. Mechanistically, machine learning-driven transcriptomics highlighted Akt2 as a candidate regulatory hub, while untargeted metabolomics, prompted by a striking hair yellowing phenotype, suggested metabolic remodeling involving the phospholipase D signaling pathway. Our findings demonstrate a promising data-driven, bottom-up rational design paradigm for advanced bioelectronic tissue repair materials.
Yue Wang, Wen Guo, Zeqi Chen et al.· Advances in Materials· 0 citations