Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation.
Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation.
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DOI：
10.7150/thno.70623
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Zhang, Shanyong
中科院分区：
文献类型：
--
作者：
Chen, Xuzhuo;Li, Chang;Cao, Xiankun;Jia, Xinlin;Chen, Xinwei;Wang, Zhenqiang;Xu, Weifeng;Dai, Fengrong;Zhang, Shanyong
基本原理：炎性巨噬细胞和破骨细胞（OCs）在关节炎症中起关键作用，其特征在于活性氧（ROS）的过度产生，导致滑膜炎症和骨侵蚀。清除活性氧，特别是通过调节线粒体代谢活性，可能是一个理想的策略，用于管理炎症关节。本研究旨在开发一种具有内源性和外源性ROS清除活性的靶向超分子药物载体，用于关节炎的治疗。研究方法：在这项研究中，我们利用锌基金属有机超容器（MOSC）作为质子海绵和电子库，具有出色的质子结合能力，细胞外ROS清除能力和生物相容性，以建立一个有效的超分子纳米载体内/溶酶体逃逸和线粒体靶向。4-衣康酸辛酯（4-OI），衣康酸衍生物，作为负载客体，用于构建炎性巨噬细胞和OC的协同治疗系统。结果如下：4-OI@Zn-NH-pyr有效包封后，不仅具有较强的ROS清除能力，而且通过介导炎症巨噬细胞的线粒体呼吸作用降低ROS的产生。关于其抗炎功效，4-OI@Zn-NH-pyr通过激活核因子红细胞2相关因子2（Nrf 2）来改善炎症反应，从而除了抑制NF-κB途径之外还增加抗氧化剂的产生。此外，核因子-κB配体受体激活剂（RANKL）诱导的破骨细胞分化和功能被4-OI@Zn-NH-pyr显著抑制。与体外观察一致，4-OI@Zn-NH-pyr在急性关节炎模型中有效抑制滑膜炎症和软骨下骨破坏。结论：通过首次使用对ROS具有高度反应性的MOSC作为载药基质，本研究通过设计具有亚细胞靶向和ROS清除能力的协同超分子药物递送系统，为严重关节炎症的管理提供了一条途径。
Rationale: Inflammatory macrophages and osteoclasts (OCs) play critical roles in joint inflammation, which feature the excessive production of reactive oxygen species (ROS), resulting in synovial inflammation and bone erosion. Scavenging ROS, especially by modulating mitochondrial metabolic activity, could be a desirable strategy for the management of inflammatory joints. This study aimed to develop a mitochondria-targeted supramolecular drug delivery system with exogenous and endogenous ROS-scavenging activities for the treatment of joint inflammation. Methods: In this study, we utilized a zinc-based metal-organic supercontainer (MOSC) as a proton sponge and electron reservoir with outstanding proton binding capacity, extracellular ROS-scavenging ability, and biocompatibility to establish an efficient supramolecular nanocarrier for endo/lysosomal escape and mitochondrial targeting. 4-Octyl itaconate (4-OI), an itaconate derivative, served as the loaded guest for the construction of a synergistic therapeutic system for inflammatory macrophages and OCs. Results: After the effective encapsulation of 4-OI, 4-OI@Zn-NH-pyr not only exhibited potent ROS-scavenging capacity, but also reduced ROS production by mediating mitochondrial respiration in inflammatory macrophages. Regarding its anti-inflammatory efficacy, 4-OI@Zn-NH-pyr ameliorated the inflammatory reaction by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thus increasing the production of antioxidants, apart from the inhibition of NF-κB pathways. Additionally, receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and function was remarkably suppressed by 4-OI@Zn-NH-pyr. Consistent with in vitro observations, 4-OI@Zn-NH-pyr efficiently inhibited synovial inflammation and subchondral bone destruction in an acute arthritis model. Conclusion: By using MOSCs that are highly reactive to ROS as drug-loaded matrices for the first time, this study provides an avenue for the management of severe joint inflammation by designing synergistic supramolecular drug-delivery systems with subcellular targeting and ROS-scavenging capacity.
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