These results demonstrate that coupling a structurally engineered scaffold with a small molecule supports multiple repair-associated responses following ischemic stroke and offers a translational strategy for repairing ischemic brain injury.
Abstract
Ischemic stroke induces acute oxidative damage followed by prolonged inflammation and incomplete tissue reconstruction, creating a need for local therapies that provide sustained neuroprotection and repair support. Here, an injectable hybrid scaffold is developed that integrates a brain-compliant hydrogel with short electrospun nanofibers for sustained local delivery of morroniside (MOR), a pleiotropic small molecule with antioxidant, anti-inflammatory and pro-regenerative activities. The hydrogel provides early MOR release to mitigate acute injury, while the nanofibers enable sustained delivery together with extracellular-matrix-mimetic cues that support angiogenesis, neurogenesis, and axonal remodeling. In vitro, MOR enhanced endothelial and neuronal survival and promoted their migration and lineage-specific differentiation under ischemic conditions. In a rat cortical stroke model, MOR-loaded scaffolds significantly improved motor recovery, reduced infarct volume, enhanced vascularization, suppressed glial scarring, and facilitated axonal regeneration. Transcriptomic analysis revealed broad microenvironmental reprogramming, including suppression of inflammatory pathways and enrichment of PI3K-AKT-related repair signaling with increased p-PI3K and p-AKT immunofluorescence. These results demonstrate that coupling a structurally engineered scaffold with a small molecule supports multiple repair-associated responses following ischemic stroke and offers a translational strategy for repairing ischemic brain injury.
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
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
Traumatic brain injury (TBI) triggers complex secondary pathologies that lack effective treatments. While mesenchymal stem cell (MSC) transplantation is promising, it is severely limited by poor cell retention and survival. To address these challenges, we engineered a combinatorial platform comprising an injectable, self-healing supramolecular gelatin hydrogel (iGel) loaded with CRISPR-SAM-engineered "Super MSCs" (SPMSCs). These cells were programmed to endogenously multiplex the activation of neuroprotective factors IL-10 and FGF21. Our results demonstrate that the biomimetic iGel niche enhances SPMSC viability and sustained factor secretion compared to 2D cultures. In a murine TBI model, iGel-encapsulated SPMSCs exerted potent immunomodulatory effects, suppressing microglial inflammation and neuronal apoptosis while restoring blood-brain barrier integrity. Furthermore, the treatment promoted angiogenesis and endogenous neurogenesis. Consequently, treated mice exhibited reduced cerebral edema and lesion volume, alongside significant improvements in sensorimotor function and spatial memory. This study establishes a versatile, gene-editing-empowered biomaterial platform that overcomes critical bottlenecks in cell therapy for central nervous system injuries.
Chao Xu, Yi Liu, Mengge Wang et al.· Advanced Healthcare Material...· 0 citations
Diabetic chronic wounds remain difficult to treat because hypoxia and insufficient regenerative signaling persist. Although live biotherapeutics offer a promising route to local oxygenation therapy, current methods largely support a single microbial function rather than coordinate microbial oxygenation with regenerative cues. Here, we report a hydrogel living therapeutic material in which a crosslinked hyaluronic acid matrix coordinates a living metabolic module of Synechococcus elongatus with a regenerative module of platelet-rich plasma (PRP). The matrix enables injectability and rapid gelation while supporting microbial metabolic activity and modulating the local retention and release of PRP-derived growth factors. The resulting material sustains oxygen generation and preserves the viability of the living module. Particularly, it reduces intracellular ROS accumulation, promotes fibroblast migration, and enhances endothelial tube formation in vitro. In diabetic wounds, it accelerates wound closure and improves re-epithelialization, collagen remodeling, and angiogenesis. Transcriptomic analysis further reveals coordinated regulation of stimulus-response, immune-related, and cytokine- and chemokine-associated pathways. This work establishes a living therapeutic material framework for integrating microbial oxygenation with regenerative signaling for pathological wound microenvironment remodeling. STATEMENT OF SIGNIFICANCE: Diabetic wounds are difficult to heal because damaged tissues often lack both oxygen and regenerative signals. Current living wound therapies mainly focus on microbial oxygen production, but they rarely coordinate oxygen supply with growth-factor-mediated tissue repair. This study develops an injectable living hydrogel that combines photosynthetic Synechococcus elongatus with platelet-rich plasma in a hyaluronic acid matrix. The material continuously generates oxygen, retains and releases regenerative factors, reduces oxidative stress, and promotes cell migration, angiogenesis, collagen remodeling, and wound closure. By integrating metabolic oxygenation with regenerative signaling, this work provides a strategy for remodeling pathological wound microenvironments and designing living therapeutic materials for chronic tissue repair.
Xi Zeng, N. Gong, Guang-Yu Zhang et al.· Acta Biomaterialia· 0 citations
The homeostasis of the Neurovascular Unit (NVU), a basic functional unit of the brain, is essential for neurological recovery. Glioblastoma-derived exosomes have been demonstrated to enhance angiogenesis under hypoxic conditions, but their reparative potential in non-tumor ischemic microenvironments remain unclear. Moreover, free Exos are limited by rapid clearance, poor lesion retention, and uncontrolled release. Herein, we prepared an injectable chitosan hydrogel loaded with A172 cell-derived Exos (H-A-Exos) for intranasal delivery and evaluated its therapeutic effects in a rat middle cerebral artery occlusion (MCAO) model. In vitro, A-Exos facilitated endothelial cell proliferation, migration, and vascular endothelial growth factor (VEGF) expression, while inhibiting NVU cell apoptosis and reducing oxidative stress and inflammatory responses. When loaded within injectable chitosan hydrogel, A-Exos exhibited enhanced retention and sustained release, resulting in improved accumulation in the ischemic infarct area following intranasal administration. Compared to the model group, H-A-Exos significantly improved behavioral recovery, as evidenced by reduced modified Neurological Severity Score (mNSS), and decreased cerebral infarct volume (13.02 ± 1.01%), showing superior efficacy to free A-Exos and Nimodipine (NMDP). Mechanistically, H-A-Exos upregulated eNOS, Bcl-2, VEGF and CD31 expression, thereby promoting vascular regeneration and NVU remodeling. Thus, these findings confirm the effective pro-angiogenic and reparative roles of A-Exos in a non-tumor ischemic microenvironment and demonstrate that intranasal H-A-Exos represents a promising therapeutic strategy for restoring NVU homeostasis and enhancing revascularization following ischemic stroke, underscoring their innovative therapeutic potential.
Lifei Huang, Zhihan Liu, Quanrui Zhang et al.· International Journal of Bio...· 0 citations