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水凝胶微针贴片负载富含干细胞的线粒体微囊泡促进慢性伤口愈合。

Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing.

机构信息

School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.

Department of Plastic and Reconstructive Surgery, The First Medical Centre, Chinese PLA General Hospital, 28 Fuxing Street, Beijing 100853, China.

出版信息

ACS Nano. 2024 Oct 1;18(39):26733-26750. doi: 10.1021/acsnano.4c06921. Epub 2024 Sep 5.

DOI:10.1021/acsnano.4c06921
PMID:39238258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11447894/
Abstract

Rescuing or compensating mitochondrial function represents a promising therapeutic avenue for radiation-induced chronic wounds. Adult stem cell efficacies are primarily dependent on the paracrine secretion of mitochondria-containing extracellular vesicles (EVs). However, effective therapeutic strategies addressing the quantity of mitochondria and mitochondria-delivery system are lacking. Thus, in this study, we aimed to design an effective hydrogel microneedle patch (MNP) loaded with stem cell-derived mitochondria-rich EVs to gradually release and deliver mitochondria into the wound tissues and boost wound healing. We, first, used metformin to enhance mitochondrial biogenesis and thereby increasing the secretion of mitochondria-containing EVs (termed "Met-EVs") in adipose-derived stem cells. To verify the therapeutic effects of Met-EVs, we established an and an model of X-ray-induced mitochondrial dysfunction. The Met-EVs ameliorated the mitochondrial dysfunction by rescuing mitochondrial membrane potential, increasing adenosine 5'-triphosphate levels, and decreasing reactive oxygen species production by transferring active mitochondria. To sustain the release of EVs into damaged tissues, we constructed a Met-EVs@Decellularized Adipose Matrix (DAM)/Hyaluronic Acid Methacrylic Acid (HAMA)-MNP. Met-EVs@DAM/HAMA-MNP can load and gradually release Met-EVs and their contained mitochondria into wound tissues to alleviate mitochondrial dysfunction. Moreover, we found Met-EVs@DAM/HAMA-MNP can markedly promote macrophage polarization toward the M2 subtype with anti-inflammatory and regenerative functions, which can, in turn, enhance the healing process in mice with skin wounds combined radiation injuries. Collectively, we successfully fabricated a delivery system for EVs, Met-EVs@DAM/HAMA-MNP, to effectively deliver stem cell-derived mitochondria-rich EVs. The effectiveness of this system has been demonstrated, holding great potential for chronic wound treatments in clinic.

摘要

拯救或补偿线粒体功能代表了一种有前途的治疗辐射诱导的慢性伤口的方法。成体干细胞的功效主要取决于含有线粒体的细胞外囊泡（EVs）的旁分泌分泌。然而，缺乏有效的治疗策略来解决线粒体的数量和线粒体传递系统的问题。因此，在这项研究中，我们旨在设计一种有效的负载干细胞衍生的富含线粒体的 EVs 的水凝胶微针贴片（MNP），以逐渐释放和将线粒体递送到伤口组织中，并促进伤口愈合。我们首先使用二甲双胍增强线粒体生物发生，从而增加脂肪来源干细胞中含有线粒体的 EVs 的分泌（称为“Met-EVs”）。为了验证 Met-EVs 的治疗效果，我们建立了 X 射线诱导的线粒体功能障碍的 和 模型。Met-EVs 通过挽救线粒体膜电位、增加三磷酸腺苷水平和减少活性线粒体转移产生的活性氧来改善线粒体功能障碍。为了维持 EVs 向受损组织的释放，我们构建了 Met-EVs@脱细胞脂肪基质（DAM）/透明质酸甲基丙烯酸（HAMA）-MNP。Met-EVs@DAM/HAMA-MNP 可以负载并逐渐将 Met-EVs 和其内含的线粒体递送到伤口组织中，以缓解线粒体功能障碍。此外，我们发现 Met-EVs@DAM/HAMA-MNP 可以显著促进巨噬细胞向具有抗炎和再生功能的 M2 亚型极化，从而增强合并辐射损伤的小鼠皮肤伤口的愈合过程。总之，我们成功地构建了一种 EVs 的递送系统，即 Met-EVs@DAM/HAMA-MNP，以有效地递送电镜细胞衍生的富含线粒体的 EVs。该系统的有效性已得到证实，在临床治疗慢性伤口方面具有很大的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/b11e031d2789/nn4c06921_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/a6ac2d77ffe4/nn4c06921_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/7dc4c5d3f222/nn4c06921_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/72c19829643c/nn4c06921_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/f52aa880117f/nn4c06921_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/e9298705bc87/nn4c06921_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/f9e55837e3d5/nn4c06921_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/86438bd8a50e/nn4c06921_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/b11e031d2789/nn4c06921_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/a6ac2d77ffe4/nn4c06921_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/7dc4c5d3f222/nn4c06921_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/72c19829643c/nn4c06921_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/f52aa880117f/nn4c06921_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/e9298705bc87/nn4c06921_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/f9e55837e3d5/nn4c06921_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/86438bd8a50e/nn4c06921_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/888f/11447894/b11e031d2789/nn4c06921_0008.jpg

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