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A Biomimetic Nanocarrier Strategy Targets Ferroptosis and Efferocytosis During Myocardial Infarction
Lin Song1, Xiaosu Yuan1, Zhonghao Zhao1
1School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
This study developed novel nanoparticles to treat myocardial infarction (MI) by inhibiting ferroptosis and enhancing cell clearance. The Fer-aCD47@PHMSN nanoparticles effectively reduced heart damage and improved cardiac function in MI models.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cardiovascular Research
Background:
- Myocardial infarction (MI) involves cardiomyocyte death, exacerbated by ferroptosis.
- Upregulated CD47 on damaged heart cells hinders macrophage clearance (efferocytosis).
- Targeting both ferroptosis and efferocytosis offers a potential therapeutic strategy for MI.
Purpose of the Study:
- To engineer platelet membrane-coated nanoparticles (Fer-aCD47@PHMSN) for targeted MI therapy.
- To encapsulate a ferroptosis inhibitor (Ferrostatin-1) and an anti-CD47 antibody.
- To evaluate the nanoparticles' efficacy in reducing cardiomyocyte death and inflammation.
Main Methods:
- Developed platelet membrane-coated hollow mesoporous silicon nanoparticles (HMSN).
- Encapsulated Ferrostatin-1 (ferroptosis inhibitor) and anti-CD47 antibody.
- Assessed nanoparticle targeting, ferroptosis inhibition, efferocytosis enhancement, and therapeutic effects in vitro and in MI mice.
Main Results:
- Platelet membrane coating enhanced nanoparticle targeting to MI sites.
- Fer-aCD47@PHMSN reduced cardiomyocyte ferroptosis by 38.5% and improved efferocytosis by 15% in vitro.
- In MI mice, treatment significantly reduced cardiomyocyte death (~30%), inflammation, and improved cardiac function.
Conclusions:
- Co-delivery of anti-ferroptosis and efferocytosis-enhancing agents via nanoparticles is effective.
- Fer-aCD47@PHMSN demonstrates a novel therapeutic strategy for targeted MI treatment.
- This approach mitigates myocardial damage and improves cardiac function post-MI.
