Li Guangyin, Chen Jianfeng, Wang Zhuo, Fu Qianqian, Tian Zhen, Liu Yingying, Ai Xin, Wang Chun, Wang Jiaxu, Yang Haobo, Yang Haichao, Shan Jiaxin, Leng Xiaoping, Tian Jiawei, Jiang Shuangquan
Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China; Ultrasound Molecular Imaging Joint Laboratory of Heilongjiang Province (International Cooperation), Harbin, 150086, China; Key Laboratories of Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Ministry of Education, Harbin, 150086, China.
Laboratory Animal Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Biomaterials. 2026 Jan;324:123494. doi: 10.1016/j.biomaterials.2025.123494. Epub 2025 Jun 10.
Donor heart-resident C-C chemokine receptor 2 (CCR2) macrophages induce the recruitment of CCR2 monocytes to a transplanted hearts through the secretion of monocyte chemoattractant protein-1 (MCP-1), which mediates the incidence of acute rejection (AR). In this study, we synthesized MCP-1 peptide-modified polyethylene glycol-poly (lactic-co-glycolic) acid (PEG-PLGA) nanoparticles loaded with the sonosensitizer dihydroporphyrin e6 (Ce6) and administered them via intramyocardial injection and used in combination with sonodynamic therapy (SDT) to selectively deplete donor cardiac-resident and infiltrating CCR2 macrophages. In vitro experiments confirmed that Ce6-NP-MCP-1 targets and has chemotactic effects on CCR2 macrophages, thereby enhancing the therapeutic efficacy of STD. In mouse heart grafts, the chemotactic effect of Ce6-NP-MCP-1 on CCR2 macrophages has been used to induce donor heart-resident and infiltrating CCR2 macrophages to aggregate and phagocytose nanoparticles in combination with SDT to induce macrophage apoptosis. This therapy inhibits the number of donor heart-resident CCR2 macrophages and downregulates the expression of proinflammatory cytokines and inflammatory infiltration. In addition, it significantly prolongs the allograft survival time. Therefore, CCR2-targeted nanoparticles combined with SDT for the selective depletion of donor heart-resident CCR2 macrophages provide a promising paradigm for AR target treatment.
供体心脏驻留的C-C趋化因子受体2（CCR2）巨噬细胞通过分泌单核细胞趋化蛋白-1（MCP-1）诱导CCR2单核细胞募集至移植心脏，MCP-1介导急性排斥反应（AR）的发生。在本研究中，我们合成了负载声敏剂二氢卟吩e6（Ce6）的MCP-1肽修饰的聚乙二醇-聚乳酸-乙醇酸共聚物（PEG-PLGA）纳米颗粒，并通过心肌内注射给药，联合声动力疗法（SDT）选择性清除供体心脏驻留及浸润的CCR2巨噬细胞。体外实验证实，Ce6-NP-MCP-1靶向CCR2巨噬细胞并具有趋化作用，从而增强了SDT的治疗效果。在小鼠心脏移植模型中，Ce6-NP-MCP-1对CCR2巨噬细胞的趋化作用已被用于诱导供体心脏驻留及浸润的CCR2巨噬细胞聚集，并与SDT联合促使巨噬细胞吞噬纳米颗粒以诱导巨噬细胞凋亡。该疗法可抑制供体心脏驻留CCR2巨噬细胞的数量，并下调促炎细胞因子的表达及炎症浸润。此外，它还能显著延长同种异体移植物的存活时间。因此，靶向CCR2的纳米颗粒联合SDT用于选择性清除供体心脏驻留的CCR2巨噬细胞为AR的靶向治疗提供了一种有前景的模式。
