Sun Huxiao, Zhan Mengsi, Zou Yu, Ma Jie, Liang Jiajia, Tang Guo, Laurent Regis, Mignani Serge, Majoral Jean-Pierre, Shi Xiangyang, Shen Mingwu
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China.
Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, CEDEX 4, 31077, Toulouse, France; Université Toulouse, 118 Route de Narbonne, CEDEX 4, 31077, Toulouse, France.
Biomaterials. 2025 May;316:122999. doi: 10.1016/j.biomaterials.2024.122999. Epub 2024 Dec 5.
Reprogramming imbalanced synovial macrophages and shaping an immune microenvironment conducive to bone and cartilage growth is crucial for efficient tackling of osteoarthritis (OA). Herein, we present a co-delivery nanosystem based on generation 2 (G2) hydroxyl-terminated bioactive phosphorus dendrimers (G2-OH) that were loaded with both catalase (CAT) and quercetin (Que). The created G2-OH/CAT@Que complexes exhibit a uniformly distributed spherical morphology with a size of 138.8 nm, possess robust stability, and induce macrophage reprogramming toward anti-inflammatory M2 phenotype polarization and antioxidation through cooperative CAT-catalyzed oxygen generation, Que-mediated mitochondrial homeostasis restoration, and inherent immunomodulatory activity of dendrimer. Such macrophage reprogramming leads to chondrocyte apoptosis inhibition and osteogenic differentiation of bone mesenchymal stem cells. Administration of G2-OH/CAT@Que to an OA mouse model results in attenuation of pathological features such as cartilage degeneration, bone erosion, and synovitis through oxidative stress alleviation and inflammatory factor downregulation in inflamed joints. Excitingly, the G2-OH/CAT@Que also polarized macrophages in adherent effusion monocytes (AEMs) extracted from joint cavity effusions of OA patients to M2 phenotype and downregulated reactive oxygen species levels in AEMs. This study suggests a promising nanomedicine formulation of phosphorus dendrimer-based co-delivery system to effectively tackle OA through the benefits of full-active ingredients of dendrimer, drug, and protein.
重编程失衡的滑膜巨噬细胞并塑造有利于骨骼和软骨生长的免疫微环境对于有效治疗骨关节炎（OA）至关重要。在此，我们展示了一种基于第2代（G2）羟基封端的生物活性磷树枝状大分子（G2-OH）的共递送纳米系统，其负载了过氧化氢酶（CAT）和槲皮素（Que）。所制备的G2-OH/CAT@Que复合物呈现出尺寸为138.8nm的均匀分布的球形形态，具有强大的稳定性，并通过CAT催化的协同产氧、Que介导的线粒体稳态恢复以及树枝状大分子固有的免疫调节活性，诱导巨噬细胞重编程为抗炎M2表型极化并具有抗氧化作用。这种巨噬细胞重编程导致软骨细胞凋亡抑制和骨间充质干细胞的成骨分化。将G2-OH/CAT@Que给予OA小鼠模型可通过减轻炎症关节中的氧化应激和下调炎症因子来减轻诸如软骨退变、骨侵蚀和滑膜炎等病理特征。令人兴奋的是，G2-OH/CAT@Que还将从OA患者关节腔积液中提取的贴壁积液单核细胞（AEMs）中的巨噬细胞极化为M2表型，并下调AEMs中的活性氧水平。这项研究表明了一种基于磷树枝状大分子的共递送系统的有前景的纳米药物制剂，可通过树枝状大分子、药物和蛋白质的全活性成分的益处有效治疗OA。
