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<p>Mesenchymal stem cell (MSC)–derived exosomes have emerged as potent pro-angiogenic therapeutics; however, their clinical translation is limited by rapid clearance, poor cellular uptake, and inadequate retention at target sites. Although hydrogel-based delivery systems have been explored to address these limitations, how viscoelastic hydrogel matrices influence exosome bioavailability and angiogenesis-related cellular responses remains insufficiently understood. In this study, a viscoelastic PEG–alginate hydrogel was developed as a sustained delivery platform for MSC-derived exosomes, and its pro-angiogenic effects were systematically investigated in human umbilical vein endothelial cells (HUVECs) and human umbilical vein smooth muscle cells (HUVSMCs). The hydrogel demonstrated excellent cytocompatibility and enabled sustained exosome release, resulting in significantly enhanced cellular uptake compared with free exosomes. Exosome-loaded hydrogels markedly promoted cell proliferation and migration in both cell types, as evidenced by CCK-8 and scratch assays. In vitro tube formation assays further revealed that hydrogel-mediated exosome delivery induced more compact and mature vascular-like networks than exosomes administered alone. Mechanistically, RT-qPCR analysis showed significant upregulation of key angiogenesis-related genes, including <i>VEGFR2</i>,<i> VEGFA</i>,<i> ANG1</i>,<i> ANG2</i>, and <i>eNOS</i>, with the highest expression observed in the hydrogel-exosome group. Under H₂O₂-induced oxidative stress, exosome-loaded hydrogels substantially reduced endothelial apoptosis, as indicated by a decrease in TUNEL-positive cells. Collectively, these findings demonstrate that viscoelastic PEG–alginate hydrogels enhance the stability, cellular uptake, and pro-angiogenic efficacy of MSC-derived exosomes while providing cytoprotective effects, highlighting their potential as an effective delivery platform for angiogenesis-mediated regenerative therapies.</p>

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Study on the physicochemical properties of MSCs exosome-loaded viscous hydrogels and their mechanism of regulating angiogenesis

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Xiaodong Yang,
  • Jianqing Deng,
  • Yuxing Zhang,
  • Yun Liu,
  • Zhigang Peng,
  • Juan Chen,
  • Kunqiu Yang,
  • Xue Li,
  • Lei Tian

摘要

Mesenchymal stem cell (MSC)–derived exosomes have emerged as potent pro-angiogenic therapeutics; however, their clinical translation is limited by rapid clearance, poor cellular uptake, and inadequate retention at target sites. Although hydrogel-based delivery systems have been explored to address these limitations, how viscoelastic hydrogel matrices influence exosome bioavailability and angiogenesis-related cellular responses remains insufficiently understood. In this study, a viscoelastic PEG–alginate hydrogel was developed as a sustained delivery platform for MSC-derived exosomes, and its pro-angiogenic effects were systematically investigated in human umbilical vein endothelial cells (HUVECs) and human umbilical vein smooth muscle cells (HUVSMCs). The hydrogel demonstrated excellent cytocompatibility and enabled sustained exosome release, resulting in significantly enhanced cellular uptake compared with free exosomes. Exosome-loaded hydrogels markedly promoted cell proliferation and migration in both cell types, as evidenced by CCK-8 and scratch assays. In vitro tube formation assays further revealed that hydrogel-mediated exosome delivery induced more compact and mature vascular-like networks than exosomes administered alone. Mechanistically, RT-qPCR analysis showed significant upregulation of key angiogenesis-related genes, including VEGFR2, VEGFA, ANG1, ANG2, and eNOS, with the highest expression observed in the hydrogel-exosome group. Under H₂O₂-induced oxidative stress, exosome-loaded hydrogels substantially reduced endothelial apoptosis, as indicated by a decrease in TUNEL-positive cells. Collectively, these findings demonstrate that viscoelastic PEG–alginate hydrogels enhance the stability, cellular uptake, and pro-angiogenic efficacy of MSC-derived exosomes while providing cytoprotective effects, highlighting their potential as an effective delivery platform for angiogenesis-mediated regenerative therapies.