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负载葡萄柚外泌体的微针系统修复肌腱修复微环境用于肌腱病治疗

Restoration of tendon repair microenvironment by grapefruit exosome-loaded microneedle system for tendinopathy therapy.

作者信息

Zhang Yuan, Zhang Ruiyang, Zhang Ti, Mu Yuhao, Juma Talante, Li Xu, Li Hao, Guo Quanyi, Cao Yongping

机构信息

Department of Orthopedics, Peking University First Hospital, Beijing, China.

Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

出版信息

Front Bioeng Biotechnol. 2025 Jul 28;13:1615650. doi: 10.3389/fbioe.2025.1615650. eCollection 2025.


DOI:10.3389/fbioe.2025.1615650
PMID:40791857
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12336195/
Abstract

Tendinitis repair remains challenging due to the limited self-renewal capacity of tenocytes and persistent inflammatory microenvironment. Conventional therapies remain limited by systemic drug toxicity and fail to coordinate immunomodulation with matrix remodeling. Plant-derived extracellular vesicles have demonstrated tissue repair potential owing to their unique bioactive components and exceptional cross-species compatibility. Nevertheless, their therapeutic role in tendon matrix regeneration remains underexplored. Here, we developed a grapefruit-derived exosome-loaded microneedle patch (MN@GF-Exos) to synergistically restored tendon structure and functions. Grapefruit-derived exosomes (GF-Exos) were loaded into dissolvable hyaluronic acid microneedles (MNs) for sustained release. GF-Exos reversed oxidative stress in tenocytes, enhancing cellular proliferation and migration, restoring collagen I synthesis, and polarizing macrophages toward M2-repair phenotypes. Transcriptomics revealed GF-Exos modulated cytokine-cytokine receptor interactions, suppressing inflammation-related pathways and activating ECM organization genes. In collagenase-induced tendinopathy mice, MN@GF-Exos enhanced gait recovery and extracellular matrix remodeling. Histology confirmed reduced fibrosis without ectopic ossification. Systemic safety was validated by unchanged organ histology and within-normal-limits serum biomarkers. This dual-functional system leverages plant exosomes' multi-component synergy and MN's spatiotemporal control, offering a translatable strategy for chronic tendon regeneration.

摘要

由于肌腱细胞的自我更新能力有限以及持续存在的炎症微环境,肌腱修复仍然具有挑战性。传统疗法受到全身药物毒性的限制,并且无法协调免疫调节与基质重塑。植物来源的细胞外囊泡由于其独特的生物活性成分和出色的跨物种兼容性而展现出组织修复潜力。然而,它们在肌腱基质再生中的治疗作用仍未得到充分探索。在此,我们开发了一种负载葡萄柚来源外泌体的微针贴片(MN@GF-Exos),以协同恢复肌腱结构和功能。将葡萄柚来源的外泌体(GF-Exos)负载到可溶解的透明质酸微针(MNs)中以实现持续释放。GF-Exos 逆转了肌腱细胞中的氧化应激,增强了细胞增殖和迁移,恢复了 I 型胶原蛋白的合成,并使巨噬细胞向 M2 修复表型极化。转录组学显示 GF-Exos 调节细胞因子-细胞因子受体相互作用,抑制炎症相关途径并激活 ECM 组织基因。在胶原酶诱导的肌腱病小鼠中,MN@GF-Exos 促进了步态恢复和细胞外基质重塑。组织学证实纤维化减少且无异位骨化。通过器官组织学未改变和血清生物标志物在正常范围内验证了全身安全性。这种双功能系统利用了植物外泌体的多组分协同作用和微针的时空控制,为慢性肌腱再生提供了一种可转化的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/461aec4c03e9/fbioe-13-1615650-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/70b23c568eda/fbioe-13-1615650-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/a1cc1edf091f/fbioe-13-1615650-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/d65044305661/fbioe-13-1615650-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/d93fcedb0e14/fbioe-13-1615650-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/9a80b9bfa57e/fbioe-13-1615650-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/1aa80636dfbe/fbioe-13-1615650-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/b1874cf856c8/fbioe-13-1615650-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/5621d136b29f/fbioe-13-1615650-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/461aec4c03e9/fbioe-13-1615650-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/70b23c568eda/fbioe-13-1615650-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/a1cc1edf091f/fbioe-13-1615650-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/d65044305661/fbioe-13-1615650-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/d93fcedb0e14/fbioe-13-1615650-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/9a80b9bfa57e/fbioe-13-1615650-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/1aa80636dfbe/fbioe-13-1615650-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/b1874cf856c8/fbioe-13-1615650-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/5621d136b29f/fbioe-13-1615650-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7ca0/12336195/461aec4c03e9/fbioe-13-1615650-g009.jpg

相似文献

[1]
Restoration of tendon repair microenvironment by grapefruit exosome-loaded microneedle system for tendinopathy therapy.

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本文引用的文献

[1]
Achilles tendinopathy.

Nat Rev Dis Primers. 2025-3-27

[2]
Soft Pneumatic Device Designed to Mimic the Periosteal Environment for Regulating the Fate of Mesenchymal Stem Cells.

Adv Healthc Mater. 2025-6

[3]
Reactive oxygen species in tendon injury and repair.

Redox Biol. 2025-4

[4]
Restoring tendon microenvironment in tendinopathy: Macrophage modulation and tendon regeneration with injectable tendon hydrogel and tendon-derived stem cells exosomes.

Bioact Mater. 2025-1-22

[5]
A systematic review of microneedles technology in drug delivery through a bibliometric and patent overview.

Heliyon. 2024-11-22

[6]
Advancements in Therapeutic Approaches for Degenerative Tendinopathy: Evaluating Efficacy and Challenges.

Int J Mol Sci. 2024-11-4

[7]
Tackling exosome and nuclear receptor interaction: an emerging paradigm in the treatment of chronic diseases.

Mil Med Res. 2024-9-26

[8]
Exosome-like nanoparticles derived from fruits, vegetables, and herbs: innovative strategies of therapeutic and drug delivery.

Theranostics. 2024

[9]
Gelatin methacryloyl microneedle loaded with 3D-MSC-Exosomes for the protection of ischemia-reperfusion.

Int J Biol Macromol. 2024-8

[10]
Biomimetic Grapefruit-Derived Extracellular Vesicles for Safe and Targeted Delivery of Sodium Thiosulfate against Vascular Calcification.

ACS Nano. 2023-12-26

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