Engineering M2 macrophage-derived exosomes modulate activated T cell cuproptosis to promote immune tolerance in rheumatoid arthritis

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2024-11-02 DOI:10.1016/j.biomaterials.2024.122943

Guoquan Wu , Tianyu Su , Peng Zhou , Rongze Tang , Xu Zhu , Jin Wang , Minghao Chao , Liying Fan , Hanrong Yan , Peng Ye , Dehong Yu , Fenglei Gao , Hongliang Chen

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引用次数: 0

Abstract

Nanomedicines for immune modulation have made advancements in the treatment of rheumatoid arthritis (RA). However, due to aberrations in patients' immune systems, inducing antigen-specific immune tolerance while halting disease progression remains a significant challenge. Here, we develop a highly targeted multifunctional nanocomplex, termed M2Exo@CuS-CitP-Rapa (M2CPR), with the aim of selectively inhibiting inflammatory immune reactions while promoting immune tolerance towards specific antigens. M2CPR specifically targets inflammatory tissues in RA, delivering CuS NPs, CitP, Rapa, and endogenous anti-inflammatory factors, thereby ameliorating the inflammatory joint microenvironment. CuS NPs induce Cuproptosis of activated T cells, whose fragments are engulfed by resident or recruited macrophages, resulting in abundant production of TGF-β. TGF-β acts synergistically with Rapa to induce the iDCs into tDCs. tDCs present CitP to Naive T cells, promoting Tregs differentiation. Tregs, in turn, produce more TGF-β, inducing tDCs differentiation, thereby establishing a cycle of immune tolerance. Through in vitro and in vivo experiments, we validate that M2CPR can induce robust and durable antigen-specific immune tolerance, offering a new paradigm for RA therapy.

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工程M2巨噬细胞衍生的外泌体调节活化T细胞杯突，促进类风湿性关节炎的免疫耐受。

用于免疫调节的纳米药物在治疗类风湿性关节炎（RA）方面取得了进展。然而，由于患者免疫系统的畸变，在诱导抗原特异性免疫耐受的同时阻止疾病进展仍是一项重大挑战。在这里，我们开发了一种高度靶向性的多功能纳米复合物，称为 M2Exo@CuS-CitP-Rapa（M2CPR），旨在选择性地抑制炎症性免疫反应，同时促进对特定抗原的免疫耐受。M2CPR 专门针对 RA 中的炎症组织，输送 CuS NPs、CitP、Rapa 和内源性抗炎因子，从而改善炎性关节微环境。CuS NPs 能诱导活化的 T 细胞发生杯突分裂，其碎片被常驻或招募的巨噬细胞吞噬，从而产生大量的 TGF-β。TGF-β 与 Rapa 协同作用，将 iDCs 诱导为 tDCs。Tregs反过来会产生更多的TGF-β，诱导tDCs分化，从而建立免疫耐受循环。通过体外和体内实验，我们验证了 M2CPR 可以诱导稳健持久的抗原特异性免疫耐受，为 RA 治疗提供了一种新的范例。

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

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.