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Purpose <p>Mitochondrial dysfunction contributes to endothelial injury in vascular diseases and interventions. While mitochondrial transplantation offers a promising therapeutic strategy, current approaches lack target specificity, efficient uptake, and long-term retention. This study presents a surface-engineering approach to enhance mitochondria delivery to the vascular endothelium as a step toward novel endothelial repair strategies.</p> Methods <p>Mitochondria were isolated from healthy induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) and surface functionalized with a phospholipid-based coating platform (DSPE-PEG) to enable peptide functionalization. DSPE-PEG was conjugated to either VCAM-1-binding peptide and collagen-binding peptide to enable targeting to dysfunctional and injured endothelium. Mitochondria particle characteristics were measured using flow cytometry, dynamic light scattering and Seahorse. Mitochondrial uptake, retention, and function were assessed in human diabetic aortic endothelial cells (DAECs) using confocal microscopy, flow cytometry, JC-1 staining, and Seahorse metabolic analysis.</p> Results <p>iPSC-MSCs provided bioenergetically competent mitochondria suitable for therapeutic delivery. DSPE-PEG surface functionalization significantly enhanced mitochondrial uptake in DAECs, compared to uncoated mitochondria. Confocal imaging and quantitative analysis revealed increased cytoplasmic retention and greater colocalization with the endogenous mitochondrial network after 24 h. Functional assays demonstrated improved mitochondrial membrane potential and sustained oxygen consumption in recipient cells, indicating enhanced host mitochondrial function following treatment with surface-engineered mitochondria.</p> Conclusions <p>This study establishes a proof-of-concept for mitochondria surface engineering to enhance mitochondria transplantation to damaged endothelium, demonstrating improved cellular uptake and bioenergetic restoration. These findings provide a foundation for developing adaptable, cell-free therapeutics for vascular disease.</p>

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Surface-Engineered Mitochondria with Targeting Potential for Endothelial Repair

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月22日

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  • Brandon Applewhite,
  • Natalia Matiuto,
  • Aurea del Carmen,
  • Bin Jiang

摘要

Purpose

Mitochondrial dysfunction contributes to endothelial injury in vascular diseases and interventions. While mitochondrial transplantation offers a promising therapeutic strategy, current approaches lack target specificity, efficient uptake, and long-term retention. This study presents a surface-engineering approach to enhance mitochondria delivery to the vascular endothelium as a step toward novel endothelial repair strategies.

Methods

Mitochondria were isolated from healthy induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) and surface functionalized with a phospholipid-based coating platform (DSPE-PEG) to enable peptide functionalization. DSPE-PEG was conjugated to either VCAM-1-binding peptide and collagen-binding peptide to enable targeting to dysfunctional and injured endothelium. Mitochondria particle characteristics were measured using flow cytometry, dynamic light scattering and Seahorse. Mitochondrial uptake, retention, and function were assessed in human diabetic aortic endothelial cells (DAECs) using confocal microscopy, flow cytometry, JC-1 staining, and Seahorse metabolic analysis.

Results

iPSC-MSCs provided bioenergetically competent mitochondria suitable for therapeutic delivery. DSPE-PEG surface functionalization significantly enhanced mitochondrial uptake in DAECs, compared to uncoated mitochondria. Confocal imaging and quantitative analysis revealed increased cytoplasmic retention and greater colocalization with the endogenous mitochondrial network after 24 h. Functional assays demonstrated improved mitochondrial membrane potential and sustained oxygen consumption in recipient cells, indicating enhanced host mitochondrial function following treatment with surface-engineered mitochondria.

Conclusions

This study establishes a proof-of-concept for mitochondria surface engineering to enhance mitochondria transplantation to damaged endothelium, demonstrating improved cellular uptake and bioenergetic restoration. These findings provide a foundation for developing adaptable, cell-free therapeutics for vascular disease.