School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.
Int J Nanomedicine. 2024 Aug 13;19:8253-8270. doi: 10.2147/IJN.S461212. eCollection 2024.
Myocardial infarction (MI) is characterized by irreversible cardiomyocyte death resulting from an inadequate supply of oxygenated blood to the myocardium. Recent studies have indicated that ferroptosis, a form of regulated cell death, exacerbates myocardial injury during MI. Concurrently, the upregulation of CD47 on the surface of damaged myocardium following MI impairs the clearance of dead cells by macrophages, thereby hindering efferocytosis. In this context, simultaneously inhibiting ferroptosis and enhancing efferocytosis may represent a promising strategy to mitigate myocardial damage post-MI.
In this study, we engineered platelet membrane-coated hollow mesoporous silicon nanoparticles (HMSN) to serve as a drug delivery system, encapsulating ferroptosis inhibitor, Ferrostatin-1, along with an anti-CD47 antibody. We aimed to assess the potential of these nanoparticles (designated as Fer-aCD47@PHMSN) to specifically target the site of MI and evaluate their efficacy in reducing cardiomyocyte death and inflammation.
The platelet membrane coating on the nanoparticles significantly enhanced their ability to successfully target the site of myocardial infarction (MI). Our findings demonstrate that treatment with Fer-aCD47@PHMSN resulted in a 38.5% reduction in cardiomyocyte ferroptosis under hypoxia, indicated by decreased lipid peroxidation and increased in vitro. Additionally, Fer-aCD47@PHMSN improved cardiomyocyte efferocytosis by approximately 15% in vitro. In MI mice treated with Fer-aCD47@PHMSN, we observed a substantial reduction in cardiomyocyte death (nearly 30%), decreased inflammation, and significant improvement in cardiac function.
Our results demonstrated that the cooperation between the two agents induced anti-ferroptosis effects and enhanced dead cardiomyocyte clearance by macrophage as well as anti-inflammation effects. Thus, our nanoparticle Fer-aCD47@PHMSN provides a new therapeutic strategy for targeted therapy of MI.
心肌梗死（MI）的特征是心肌供氧不足导致心肌细胞不可逆转的死亡。最近的研究表明，铁死亡作为一种受调控的细胞死亡形式，会加重 MI 期间的心肌损伤。同时，MI 后受损心肌表面 CD47 的上调会损害巨噬细胞清除死亡细胞的能力，从而阻碍细胞吞噬作用。在这种情况下，同时抑制铁死亡和增强细胞吞噬作用可能是减轻 MI 后心肌损伤的一种有前途的策略。
在这项研究中，我们设计了血小板膜包覆的中空介孔硅纳米粒子（HMSN）作为药物递送系统，封装铁死亡抑制剂 Ferrostatin-1 以及抗 CD47 抗体。我们旨在评估这些纳米粒子（命名为 Fer-aCD47@PHMSN）特异性靶向 MI 部位的潜力，并评估它们在减少心肌细胞死亡和炎症方面的疗效。
纳米粒子表面的血小板膜涂层显著增强了它们成功靶向心肌梗死（MI）部位的能力。我们的研究结果表明，在缺氧条件下，Fer-aCD47@PHMSN 治疗可使心肌细胞铁死亡减少 38.5%，脂质过氧化减少，体外试验中细胞存活率提高。此外，Fer-aCD47@PHMSN 可使体外心肌细胞吞噬作用提高约 15%。在接受 Fer-aCD47@PHMSN 治疗的 MI 小鼠中，我们观察到心肌细胞死亡（减少近 30%）、炎症减轻和心脏功能显著改善。
我们的结果表明，两种药物的协同作用诱导了抗铁死亡效应，并增强了巨噬细胞清除死亡心肌细胞的能力以及抗炎作用。因此，我们的纳米粒子 Fer-aCD47@PHMSN 为 MI 的靶向治疗提供了一种新的治疗策略。
