CD80 Antibody and MTX Co-Engineered Extracellular Vesicles Targets CD80⁺ Macrophages to Suppress Inflammation and Alleviate Chronic Inflammatory Diseases.

IF 6.6 2区医学 Q1 NANOSCIENCE & NANOTECHNOLOGY

International Journal of Nanomedicine Pub Date : 2025-05-21 eCollection Date: 2025-01-01 DOI:10.2147/IJN.S517357

Jianhua Yang, Handan Zhang, Wenzhe Wang, Qiqi Yin, Xiaoning He, Dihao Tao, Hanzhe Wang, Wenhao Liu, Yiming Wang, Zhiwei Dong, Xin Chen, Bei Li

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引用次数: 0

Abstract

Introduction: Aberrant interaction between innate immune and adaptive immune cells can disrupt tissue homeostasis, consequently triggering chronic inflammatory diseases such as rheumatoid arthritis (RA) and periodontitis (PD). Pro-inflammatory macrophages serve as critical mediators in the early immune response, constituting a major population of CD80⁺ cells, while anti-inflammatory macrophages modulating inflammatory processes through the secretion of transforming growth factor-beta (TGF-β). This cytokine facilitates the differentiation of peripheral regulatory T cells (Tregs) and contributes to the establishment of immune tolerance. However, there are no definitive therapies to reshape the tissue homeostasis between innate immune and adaptive immune cells.

Methods: (1) anti-CD80-MTX-EVs was obtained by gradient centrifugation, which were characterized by TEM and DLS, and the associated membrane proteins were identified by Western Blot. (2) The mouse bone marrow-derived macrophages were co-cultured separately with EVs, anti-CD80-EVs, and anti-CD80-MTX-EVs in vitro, and the expression of CD80 on the macrophages surface as well as the proportion of Treg cell generation were detected. (3) EVs, anti-CD80-EVs and anti-CD80-MTX-EVs were injected into mice models of arthritis and periodontitis for treatment, the therapeutic effect was evaluated by the expressions of related cytokines, staining of HE, the proportion of CD80⁺ macrophages and the phenotypic differentiation of T cells in the tissues.

Results: We successfully constructed engineered EVs (anti-CD80-MTX-EVs) targeting inflammatory macrophages for intracellular MTX delivering, which inducing the anti-inflammatory transformation while upregulating the expression of TGF-β of macrophages. Furthermore, our findings demonstrate that anti-CD80-MTX-EVs effectively reduce CD80⁺ macrophage levels, promote Treg cell generation, and inhibit Th1 cell production in vivo.

Conclusion: In this study, the anti-CD80-MTX-Evs demonstrated significant therapeutic effects in both rheumatoid arthritis and periodontitis models through a triple mechanism: reducing CD80⁺ macrophage population, enhancing Treg cell differentiation, and suppressing Th1 cell development. Overall, this study presents an innovative strategy for resolving inflammation within chronic inflammatory diseases.

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CD80抗体和MTX协同工程细胞外囊泡靶向CD80+巨噬细胞抑制炎症和缓解慢性炎性疾病

先天免疫细胞和适应性免疫细胞之间的异常相互作用可以破坏组织稳态，从而引发慢性炎症性疾病，如类风湿关节炎（RA）和牙周炎（PD）。促炎巨噬细胞是早期免疫反应的关键介质，是CD80+细胞的主要群体，而抗炎巨噬细胞通过分泌转化生长因子-β (TGF-β)调节炎症过程。这种细胞因子促进外周调节性T细胞（Tregs）的分化，并有助于建立免疫耐受。然而，目前还没有明确的治疗方法来重塑先天免疫细胞和适应性免疫细胞之间的组织稳态。方法：(1)梯度离心获得抗cd80 - mtx - evs，用TEM和DLS对其进行表征，并用Western Blot对相关膜蛋白进行鉴定。(2)将小鼠骨髓源性巨噬细胞与体外培养的EVs、抗CD80-EVs、抗CD80- mtx -EVs分别共培养，检测巨噬细胞表面CD80的表达及Treg细胞生成比例。(3)将EVs、抗CD80-EVs和抗CD80- mtx -EVs分别注射到关节炎和牙周炎小鼠模型中进行治疗，通过组织中相关细胞因子的表达、HE染色、CD80+巨噬细胞比例和T细胞的表型分化来评价其治疗效果。结果：成功构建了靶向炎性巨噬细胞的工程化EVs (anti-CD80-MTX-EVs)，在细胞内传递MTX，诱导巨噬细胞抗炎转化，同时上调TGF-β的表达。此外，我们的研究结果表明，抗CD80- mtx - ev在体内有效降低CD80+巨噬细胞水平，促进Treg细胞的产生，抑制Th1细胞的产生。结论：在本研究中，抗CD80- mtx - ev通过减少CD80+巨噬细胞数量、增强Treg细胞分化和抑制Th1细胞发育的三重机制，在类风湿关节炎和牙周炎模型中均表现出显著的治疗作用。总的来说，本研究提出了一种解决慢性炎症性疾病炎症的创新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY

CiteScore

14.40

自引率

3.80%

发文量

511

审稿时长

1.4 months

期刊介绍： The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.