CTLA-4 nanovesicles disrupt dendritic cell-driven CD8 T cell priming for myocardial infarction therapy

IF 11.5 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Shengnan Wang , Mengting Li , Han Shen , Wenjing Zhou , Jiuyuan Sun , Qingsong Tang , Hongman Liu , Wencheng Zhang , Zhenya Shen , Weiqian Chen
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引用次数: 0

Abstract

Myocardial infarction (MI) remains a formidable global health challenge, as current therapies are hindered by excessive inflammation that exacerbates cardiac dysfunction and accelerates disease progression. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and CD28 are T-lymphocyte receptors with opposing roles in T-cell activation: CD28 binding to CD80/CD86 ligands on dendritic cells (DCs) mediates co-stimulation, whereas CTLA-4 engagement delivers inhibitory signals. In our present study, mannosylated cytotoxic T-lymphocyte antigen 4 (CTLA-4)-presenting small extracellular vesicles (CM@sEVs) were engineered for targeted MI therapy. By disrupting the CD80/86-CD28 costimulatory signaling, these CM@sEVs counteract dendritic cell (DC)-driven CD8+ T cell priming, thereby mitigating ischemic immunopathology while supporting myocardial repair. Notably, distinct from existing T-cell modulatory therapies, our CM@sEVs uniquely reshape in vivo T-cell dynamics directly through DC-dependent mechanisms, offering a precise and stable strategy for ischemic cardiomyopathy.

Abstract Image

Abstract Image

CTLA-4纳米囊泡破坏树突状细胞驱动的CD8 T细胞启动心肌梗死治疗
心肌梗死(MI)仍然是一个巨大的全球健康挑战,因为目前的治疗受到过度炎症的阻碍,炎症会加剧心功能障碍并加速疾病进展。细胞毒性t淋巴细胞抗原4 (CTLA-4)和CD28是t淋巴细胞受体,在t细胞活化中具有相反的作用:CD28与树突状细胞(DCs)上的CD80/CD86配体结合介导共刺激,而CTLA-4结合则传递抑制信号。在我们目前的研究中,甘露糖基化细胞毒性t淋巴细胞抗原4 (CTLA-4)呈递小细胞外囊泡(CM@sEVs)被设计用于靶向心肌梗死治疗。通过破坏CD80/86-CD28共刺激信号,这些CM@sEVs抵消树突状细胞(DC)驱动的CD8+ T细胞启动,从而减轻缺血免疫病理,同时支持心肌修复。值得注意的是,与现有的t细胞调节疗法不同,我们的CM@sEVs通过dc依赖机制直接重塑体内t细胞动力学,为缺血性心肌病提供了精确和稳定的策略。
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来源期刊
Journal of Controlled Release
Journal of Controlled Release 医学-化学综合
CiteScore
18.50
自引率
5.60%
发文量
700
审稿时长
39 days
期刊介绍: The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.
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