Liang Xiaoyu, Zhang Yang, Wang Changduo, Li Huiyang, Li Quan, Ye Yicong, Tu Chenchen, Zhao Xiliang, Yang Jing, Zeng Yong
Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
State Key Laboratory of Advanced Medical Materials and Devices, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300192, China.
Mater Today Bio. 2025 May 22;32:101899. doi: 10.1016/j.mtbio.2025.101899. eCollection 2025 Jun.
The microenvironment characterized by inflammation and oxidative stress plays a crucial role in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury. The death receptor 5 fusion protein (sDR5-Fc) specifically targets and blocks the key protein-tumor necrosis factor related apoptosis inducing ligand (TRAIL), which is involved in cell apoptosis. This study focuses on the development of reactive oxygen species (ROS) intelligent responsive sDR5-Fc nanoparticles, aimed at improving the pathological microenvironment associated with oxidative stress and inflammatory damage, inhibiting myocardial cell apoptosis while worsening, and enhancing the bioavailability and selectivity of sDR5-Fc. The successful synthesis of 6S-PLGE-PO-PEG was verified through infrared nuclear magnetic resonance and other analytical experiments. The ROS intelligent responsive sDR5-Fc nanoparticles (DPP) were successfully constructed , exhibiting a particle size of approximately 200 nm, as well as a certain stability and HO responsive release ability. DPP demonstrated good biocompatibility. The cell viability and apoptosis assays indicated that DPP significantly reduced myocardial cell damage caused by hypoxia reoxygenation and decreased cell apoptosis. In myocardial I/R rat model, the administration of DPP nanoparticle displayed superior therapeutic effects compared to the sDR5-Fc group, evidenced by the reduction in myocardial infarction area, improvement in fibrosis, decreased myocardial cell apoptosis, increased cell proliferation, enhanced angiogenesis, and inhibition of myocardial hypertrophy. The synergistic effect of ROS responsive sDR5-Fc nanoparticles in mitigating I/R injury is expected to provide a new interdisciplinary treatment approach.
以炎症和氧化应激为特征的微环境在心肌缺血再灌注（I/R）损伤的发病机制中起关键作用。死亡受体5融合蛋白（sDR5-Fc）特异性靶向并阻断关键蛋白——肿瘤坏死因子相关凋亡诱导配体（TRAIL），该配体参与细胞凋亡。本研究聚焦于活性氧（ROS）智能响应型sDR5-Fc纳米颗粒的研发，旨在改善与氧化应激和炎性损伤相关的病理微环境，抑制心肌细胞凋亡恶化，同时提高sDR5-Fc的生物利用度和选择性。通过红外核磁共振等分析实验验证了6S-PLGE-PO-PEG的成功合成。成功构建了ROS智能响应型sDR5-Fc纳米颗粒（DPP），其粒径约为200nm，具有一定的稳定性和对HO的响应释放能力。DPP表现出良好的生物相容性。细胞活力和凋亡检测表明，DPP显著降低了缺氧复氧引起的心肌细胞损伤，并减少了细胞凋亡。在心肌I/R大鼠模型中，与sDR5-Fc组相比，给予DPP纳米颗粒显示出更好的治疗效果，表现为心肌梗死面积减小、纤维化改善、心肌细胞凋亡减少、细胞增殖增加、血管生成增强以及心肌肥大受到抑制。ROS响应型sDR5-Fc纳米颗粒在减轻I/R损伤方面的协同作用有望提供一种新的跨学科治疗方法。
