Background: Tenascin-C (TNC) is an extracellular matrix (ECM) protein involved in tissue damage and fibrosis. Chimeric antigen receptor (CAR) cell therapy is a novel therapeutic approach that has attracted increasing attention in recent years. Here, we engineered CAR-macrophages targeting TNC (TNC-CAR-Ms) and explored the underlying mechanism through which TNC-CAR-Ms treat liver fibrosis.
Methods: The role of TNC in liver fibrosis was studied in established Tnc knockout (KO) and littermate control mice. A TNC-targeted single-chain variable fragment (scFv) was designed to generate TNC-CAR-Ms and evaluate their biological function. The phagocytosis and killing effects of TNC-CAR-Ms were tested in vitro, while the antifibrotic efficacy and safety of TNC-CAR-Ms were evaluated in vivo. The underlying mechanism through which TNC-CAR-Ms treat liver fibrosis was investigated by Western blotting, flow cytometry, and RNA sequencing.
Results: TNC expression was significantly upregulated in the liver and activated hepatic stellate cells (HSCs) in carbon tetrachloride (CCl4)-treated mice. Animal studies showed that Tnc KO protects mice from CCl4-induced liver damage and fibrosis. Upon demonstrating their ability to engulf and kill activated HSCs, we intravenously administered TNC-CAR-Ms to fibrotic mice and found that TNC-CAR-Ms significantly reduced liver fibrosis. Mechanistically, TNC-CAR-Ms specifically migrated to liver tissues, potently reduced TNC expression, and decreased the activity of the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) and integrin/focal adhesion kinase (FAK) signaling pathway. In addition, TNC-CAR-Ms significantly modified the hepatic immune microenvironment, characterized mainly by an increase in the numbers of M2-polarized macrophages and CD8+ T cells in the liver. Finally, in CCl4-treated mice, the depletion of CD8+ T cells with an anti-CD8α antibody significantly impaired the antifibrotic effect of TNC-CAR-Ms.
Conclusions: Our proof-of-concept study demonstrates the therapeutic potential of TNC-CAR-Ms in alleviating liver fibrosis and may inform the development of future therapeutic strategies for the treatment of a range of liver diseases with a fibrotic phenotype.
Systemic complications are common after acute brain injury (ABI) and may trigger coagulation cascades, systemic inflammation, as well as dysfunction of the cardiovascular, respiratory, and gastrointestinal systems, etc. The pathogenesis of these systemic manifestations is multifactorial but not yet fully elucidated. This paper introduces the novel term neurogenic organ dysfunction syndrome (NODS) to characterize systemic instability arising from internal and external perturbations of the neuronal center following ABI. Elucidating the central neurogenic mechanisms of NODS is critical for early detection and prevention of complications, thereby reducing mortality and improving patient outcomes following ABI. In this paper, we explore the potential central neurogenic mechanisms of NODS from the perspective of complex brain network theory, focusing on the structural network of the central autonomic system (CAS) that maintains systemic stability, and the functional network governed by the central stress system (CSS). The CAS can be divided into the cortical autonomic network, which involves higher cortical regions, and the subcortical autonomic network, which is relatively conserved, with its main connections located in deep brain structures. The CSS is a large-scale complex network characterized by hierarchy, hubs, and modularity, which together enable the competitive optimization of functional segregation and integration. Under physiological conditions, modules (mediating functional segregation) and hubs (functional integration) within the CSS dynamically trade-off with each other to maintain the overall homeostasis. However, this balance is disrupted following pathological insults or injury, resulting in weakened functional integrity of the CSS following ABI, impaired module activity, and disturbed hub integration. This paper also demonstrates the distinct pathological manifestations arising from disturbances at different levels of the homeostatic system. Finally, this study proposes potential clinical interventions, including analgesia and sedation, neuromodulation, and receptor regulation, for early interventions and potential treatment of NODS, aiming to improve patient outcomes.
Immunotherapy for cardiovascular diseases (CVDs) holds great promise for precision management by modulating localized immune-inflammatory responses. The interplay between focal cardiovascular pathology and panvascular disease, necessitates highly integrated therapeutic strategies. Nano-technology-based theranostic platforms address this challenge by enabling both regulation and real-time imaging of immune cell activity within cardiovascular lesions. These functional nanotherapy systems not only halt disease progression at pathological sites but also reduce secondary cardiovascular events driven by shared inflammatory mechanisms. Additionally, nanoplatform-based dynamic visualization of immune cell responses facilitates adaptive, personalized interventions. This review introduces the role of immune cells in CVDs. It summarizes recent advances in nanomaterial-based immunomodulation strategies, including mechanisms of immune regulation, enhanced imaging, and therapeutic applications in atherosclerosis, myocardial infarction, ischemic stroke, abdominal aortic aneurysm, and myocarditis. Collectively, this integrated nanotheranostic paradigm establishes a robust foundation for the next generation of cardiovascular precision medicine.
Venous thromboembolism (VTE) management in adult burn patients has become a crucial focus in China. The intricate nature of VTE necessitates specialized anticoagulation strategies due to the unique challenges posed by burn injuries. To address this pressing issue, the Burn and Trauma Branch of the Chinese Geriatric Medical Association and Critical Care Group of Burn Surgery Branch of the Chinese Medical Association organized a panel of domestic experts in burn surgery, critical care medicine, vascular surgery, nursing, and health statistics and methodology from Chinese hospitals to discuss VTE-related issues in burn injury, the heightened risk factors such as extensive tissue damage and prolonged immobilization, and the delicate balance required in anticoagulation therapy to mitigate bleeding risks. Based on the latest available research evidence as well as the clinical experience of the panel experts, this consensus comprehensively evaluates factors such as generalizability, suitability, and the potential implications for resource allocation. It also appropriately weighs the clinical advantages against possible drawbacks, resulting in the formulation of 21 guideline recommendations.Registration Practice Guideline REgistry for transPAREncy (PREPARE): No. 2023CN656.
Cancer neuroscience, an emerging convergent discipline, offers novel insights into the dynamic interplay between the nervous system and cancer progression. Bidirectional signaling between the nervous system and tumors, particularly within the innervated tumor microenvironment (TME), modulates key cancer hallmarks, including proliferation, immune evasion, angiogenesis, and metastasis. Neural ablation shows heterogeneous outcomes depending on nerve subtype and tumor context, underscoring the importance of nerve-type-specific and context-dependent therapeutic approaches. These mechanistic advances are catalyzing novel therapeutic strategies that target neural-TME interactions through the integration of neuroscience and oncology. Here, we highlight recent progress in cancer neuroscience and propose revised therapeutic frameworks aimed at the neuro-innervated TME. These strategies employ interdisciplinary approaches, such as drug repurposing [β-adrenergic receptor (β-AR) blockers, antipsychotics, antidepressants], and nanotechnology-enabled targeted delivery. Both preclinical and clinical data support the potential of neural-targeted therapies to improve precision, circumvent drug resistance, and enhance clinical outcomes. By bridging neuroscience and oncology, this framework delineates a translational pathway for harnessing neural-tumor crosstalk, presenting a promising avenue for advancing cancer therapeutics and improving patient care.
Background: Traumatic amputations have increased worldwide over the past two decades and are expected to increase by 72% by 2050. Surgical replantation provides superior functional recovery and patient satisfaction but is limited to specialized centers and restricted by short ischemia times, due to life-over-limb prioritization in patient care. To overcome these limitations, we developed an ex vivo limb perfusion system (EVEP) to extend limb viability and, for the first time, investigate its impact on peripheral nerve regeneration, a key prerequisite for functional recovery following replantation.
Methods: Hind limbs of 6 healthy pigs were amputated, and after 2 h of warm ischemia, limbs were either perfused normothermally for 6 h with PerfadexPlus® ± medication using in-house developed EVEP or stored statically (4 °C vs. room temperature). Perfusion parameters, blood gas analysis, serum markers, cytokine levels, thermal imaging, colloid oncotic pressure, weight gain, joint mobility, peripheral nerve histomorphometric and stereological analyses were performed.
Results: Data confirm a valid and reliable EVEP with an optimized perfusion protocol. Comparison of perfusion groups revealed lower serum injury markers in the medication group, which included methylprednisolone treatment. Additionally, the medication group exhibited reduced weight gain and preserved unrestricted joint mobility, but concurrently led to a significant decrease in pro-regenerative cytokine levels associated with Wallerian degeneration (WD).
Conclusions: In general, EVEP mitigates ischemia-related damage and facilitates ex vivo induction of WD, a critical prerequisite for nerve regeneration, functional recovery, and prevention of neuroma formation with subsequent phantom pain, by establishing the pro-regenerative environment for WD, which is further amplified by omitting the anti-inflammatory methylprednisolone.
Background: Diabetic foot ulcers (DFU), perpetually trapped in a vicious cycle of inflammation and ischemia, remain a significant clinical challenge. Exosomes (Exo) therapy holds promise for tissue repair, yet its functional potency and delivery efficiency are often limited.
Methods: We proposed an integrated strategy combining trace elements (TE) programming, Exo engineering, and intelligent delivery to overcome both functional and delivery constraints. Multiple TE (Fe, Mg, Zn, Mn, and Se) were incorporated into a three-dimensional (3D) dynamic culture system to construct high-activity engineered Exo (3D-TE-Exo). The biological mechanisms were explored via transcriptomics, mitochondrial function assays, and oxidative stress analyses. A dual-network hydrogel, incorporating dynamic Schiff base bonds and ultraviolet (UV)-triggered disulfide bond reorganization, was developed for precise and sustained Exo release in vivo.
Results: 3D-TE-Exo achieved a yield of 1.9 × 1012 particles/ml, representing a 29-fold increase over conventional culture (6.5 × 1010 particles/ml). These Exo modulated the complement pathway, restored mitochondrial membrane potential, enhanced adenosine triphosphate (ATP) production, and activated autophagy, thereby alleviating oxidative stress, with complement 1q binding protein (C1QBP) identified as a key mediator. The hydrogel enabled prolonged Exo retention and controlled release at the wound site. In DFU rat models, this system achieved 89.71% wound closure by day 14, significantly higher than the 50.64% observed in controls.
Conclusions: This study presents a synergistic approach integrating engineered Exo and smart biomaterials to accelerate DFU healing. The platform offers a multi-target intervention strategy with strong translational potential for the clinical management of chronic wounds.
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