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Peer-reviewedCC BY-NCScience Advances

Targeting the ENO1 metabolic checkpoint via microenvironment-responsive nanotherapeutics promotes postinfarction cardiac repair

  • Ruoshui Li1,2,3,4
  • Gaoyang Li1,2,3
  • Jie Li3,5,6
  • Zekun Lou1,2
  • Xuerou Jin3,5,6
  • Jun Yan1,2
  • Hongping Chen1,2
  • Fang Zhang7
  • Xiaoran Deng3,5,6,8
  • Tongda Xu1,2
8 affiliations
  1. 1Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  2. 2Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  3. 3Jiangsu Province Key Laboratory in Anesthesiology and Brain Science, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  4. 4Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China.
  5. 5School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  6. 6Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  7. 7Internal Medicine Department, Richmond University Medical Center, 355 Bard Ave, Staten Island, NY, USA.
  8. 8The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Abstract

Myocardial infarction (MI) triggers persistent inflammatory dysregulation, wherein macrophages undergo glycolytic reprogramming and adopt an inflammatory phenotype that impairs cardiac repair. However, the specific metabolic drivers underlying post-MI macrophage dysfunction remain unclear. Here, we identify enolase 1 (ENO1)-a glycolytic enzyme up-regulated in post-MI macrophages-as a critical regulator of macrophage metabolic fate and inflammatory function. To intervene, we engineered an acid-responsive nanocarrier (PECS) that externalizes phosphatidylserine within the acidic infarct microenvironment, facilitating selective macrophage uptake. Intracellular delivery of siENO1 suppressed glycolytic flux, thereby curbing lactate accumulation and relieving its metabolic inhibition of KLF4, which initiated anti-inflammatory reprogramming. In vivo, PECS-loaded siENO1 (siENO1@PECS) treatment attenuated infarct size, fibrosis, and cardiomyocyte apoptosis while improving ventricular function. Collectively, these findings identify ENO1 as a critical metabolic checkpoint in post-MI macrophage regulation and demonstrate a bioresponsive nanocarrier strategy for precise gene modulation to enhance cardiac repair.

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Cite

BibTeXRIS
BibTeX
@article{li2026targeting,
  title = {{Targeting the ENO1 metabolic checkpoint via microenvironment-responsive nanotherapeutics promotes postinfarction cardiac repair}},
  author = {Ruoshui Li and Gaoyang Li and Jie Li and Zekun Lou and Xuerou Jin and Jun Yan and Hongping Chen and Fang Zhang and Xiaoran Deng and Tongda Xu},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeg3270},
  url = {https://www.science.org/doi/10.1126/sciadv.aeg3270},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Targeting the ENO1 metabolic checkpoint via microenvironment-responsive nanotherapeutics promotes postinfarction cardiac repair
AU  - Ruoshui Li
AU  - Gaoyang Li
AU  - Jie Li
AU  - Zekun Lou
AU  - Xuerou Jin
AU  - Jun Yan
AU  - Hongping Chen
AU  - Fang Zhang
AU  - Xiaoran Deng
AU  - Tongda Xu
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aeg3270
UR  - https://www.science.org/doi/10.1126/sciadv.aeg3270
AB  - Myocardial infarction (MI) triggers persistent inflammatory dysregulation, wherein macrophages undergo glycolytic reprogramming and adopt an inflammatory phenotype that impairs cardiac repair. However, the specific metabolic drivers underlying post-MI macrophage dysfunction remain unclear. Here, we identify enolase 1 (ENO1)-a glycolytic enzyme up-regulated in post-MI macrophages-as a critical regulator of macrophage metabolic fate and inflammatory function. To intervene, we engineered an acid-responsive nanocarrier (PECS) that externalizes phosphatidylserine within the acidic infarct microenvironment, facilitating selective macrophage uptake. Intracellular delivery of siENO1 suppressed glycolytic flux, thereby curbing lactate accumulation and relieving its metabolic inhibition of KLF4, which initiated anti-inflammatory reprogramming. In vivo, PECS-loaded siENO1 (siENO1@PECS) treatment attenuated infarct size, fibrosis, and cardiomyocyte apoptosis while improving ventricular function. Collectively, these findings identify ENO1 as a critical metabolic checkpoint in post-MI macrophage regulation and demonstrate a bioresponsive nanocarrier strategy for precise gene modulation to enhance cardiac repair.
SN  - 2375-2548
ER  -