巨噬细胞靶向二氧化锰纳米激动剂介导的cgas介导的抗结核抗菌免疫治疗。

IF 9.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia Pub Date : 2025-04-01 DOI:10.1016/j.actbio.2025.03.002

Kangsheng Liao , Ruihong Chen , Jinwei Zhang , Yongdui Ruan , Xueqin Huang , Yuhe Huang , Jiaojiao Xia , Daina Zhao , Lingming Chen , Yi Zhao , Fen Yang , Jun-Fa Xu , Ling Shen , Jiang Pi

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引用次数: 0

摘要

由结核分枝杆菌（Mtb）感染引起的结核病（TB）仍然是传染病中的头号杀手之一。结核的发病机制特点是结核分枝杆菌复杂的免疫逃逸机制和抗结核药物的低靶向作用。cGAS信号通路负责触发宿主对结核分枝杆菌感染的抗菌免疫，已显示出作为抗结核免疫治疗靶点的潜力。由于cGAS激动剂锰离子（Mn2+）可以激活cGAS介导的自噬来抑制巨噬细胞内的结核分枝杆菌，我们基于二氧化锰纳米颗粒构建了一种靶向cGAS信号的功能性纳米激动剂，命名为Tuf-Rif@HA-MnO2 NPs，用于协同巨噬细胞靶向药物递送和抗结核免疫治疗。Tuf-Rif@HA-MnO2 NPs可以主动靶向巨噬细胞递送利福平，并与细胞内谷胱甘肽（GSH）反应释放Mn2+，激活cGAS-STING信号，进一步促进Mtb感染巨噬细胞的自噬和抗菌M1极化，实现胞内协同清除Mtb。此外，Tuf-Rif@HA-MnO2 NPs可以促进体内树突状细胞成熟、CD4+ Th1细胞和CD8+细胞毒性T细胞活化，这些共同导致Mtb感染小鼠的肺部组织炎症减轻，且无全身毒性。该巨噬细胞靶向药物递送纳米激动剂系统有望开发针对cGAS信号的合理免疫治疗策略，用于治疗结核病和耐药结核病。意义说明：cgas介导的自噬在巨噬细胞的Mtb清除中起关键作用。Tuf-Rif@HA-MnO2 NPs特异性地将利福平输送到巨噬细胞中清除结核分枝杆菌。Tuf-Rif@HA-MnO2 NPs激活cgas介导的巨噬细胞自噬清除Mtb。Tuf-Rif@HA-MnO2 NPs协同cgas介导的免疫治疗与靶向药物递送，更有效地抗结核治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

cGAS-mediated antibacterial immunotherapy against tuberculosis by macrophage-targeted manganese dioxide nanoagonist

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cGAS-mediated antibacterial immunotherapy against tuberculosis by macrophage-targeted manganese dioxide nanoagonist

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases. The pathogenesis hallmarks for TB are complex immune escape mechanisms of Mtb and low targeting effects of anti-TB drugs. cGAS signaling, which is responsible for triggering host antibacterial immunity against Mtb infection, has shown potentials to serve as targets for anti-TB immunotherapy. As cGAS agonist manganese ions (Mn²⁺) can activate cGAS-mediated autophagy to inhibit intracellular Mtb in macrophages, we constructed a functional nanoagonist targeting cGAS signaling based on manganese dioxide nanoparticles, naming Tuf-Rif@HA-MnO₂ NPs, for synergistic macrophage-targeted drug delivery and anti-TB immuno-therapeutics. Tuf-Rif@HA-MnO₂ NPs can actively target macrophages for rifampicin delivery and react with intracellular glutathione (GSH) to release Mn²⁺ for cGAS-STING signaling activation, which further promote autophagy and antibacterial M1 polarization of Mtb infected macrophages to achieve synergistic intracellular Mtb clearance. Furthermore, Tuf-Rif@HA-MnO₂ NPs can potentiate dendritic cell maturation, CD4+ Th1 cell and CD8+ cytotoxic T cell activation in vivo, which collectively attribute to reduced Mtb burdens and alleviated tissue inflammations in lung of Mtb-infected mice without systemic toxicity. This macrophage targeted drug delivery nanoagonist system is expected to develop rational immunotherapy strategy targeting cGAS signaling against TB and drug-resistant TB.

Statement of Significance

cGAS-mediated autophagy plays a critical role in Mtb clearance in macrophages.

Tuf-Rif@HA-MnO₂ NPs specifically deliver rifampicin into macrophage for Mtb clearance.

Tuf-Rif@HA-MnO₂ NPs activate cGAS-mediated macrophage autophagy for Mtb clearance.

Tuf-Rif@HA-MnO₂ NPs synergize cGAS-mediated immunotherapy with targeted drug delivery for more effective anti-TB treatment.

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来源期刊

Acta Biomaterialia 工程技术-材料科学：生物材料

CiteScore

16.80

自引率

3.10%

发文量

776

审稿时长

30 days

期刊介绍： Acta Biomaterialia is a monthly peer-reviewed scientific journal published by Elsevier. The journal was established in January 2005. The editor-in-chief is W.R. Wagner (University of Pittsburgh). The journal covers research in biomaterials science, including the interrelationship of biomaterial structure and function from macroscale to nanoscale. Topical coverage includes biomedical and biocompatible materials.