Surface-Functionalized Stem Cell-Derived Extracellular Vesicles for Vascular Elastic Matrix Regenerative Repair.
Surface-Functionalized Stem Cell-Derived Extracellular Vesicles for Vascular Elastic Matrix Regenerative Repair.
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DOI：
10.1021/acs.molpharmaceut.2c00769
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发表时间：
2023-06-05
影响因子：
4.9
通讯作者：
Ramamurthi, Anand
中科院分区：
文献类型：
--
作者：
Sajeesh, S.;Camardo, Andrew;Dahal, Shataakshi;Ramamurthi, Anand
细胞外囊泡（EVs）是一种携带细胞特异性生物分子信息的纳米级囊泡。我们之前的研究表明，成人骨髓间充质干细胞（BM-MSC）衍生的EVs在来自弹性酶注入的大鼠腹主动脉瘤（AAA）模型的平滑肌细胞（SMCs）培养物中具有抗蛋白水解和促再生作用，这有望成为治疗主动脉壁自然不可逆弹性基质畸变的治疗平台。由于系统给药的ev很难进入组织损伤部位，因此提高其对靶组织亲和力的疾病策略对ev治疗策略具有重要意义。为了实现这一目标，在这项工作中，我们开发了一种定位表面修饰策略，将msc衍生的电动汽车靶向到AAA壁上。这些ev与一个短的、合成的、叠氮修饰的肽序列表面偶联，以靶向结合组织蛋白酶K (CatK)，这是一种在AAA壁上过表达的半胱氨酸蛋白酶。使用无铜点击化学方法进行偶联。我们确定这种结合提高了体外培养的动脉瘤SMCs对EV的吸收，以及它们与基质损伤血管壁的结合。多肽偶联后，msc - ev对培养的大鼠动脉瘤SMCs的促再生和抗蛋白水解作用也不受影响。从这项研究来看，用短合成肽序列进行修饰似乎是一种有效的策略，可以改善细胞对ev的特异性摄取，并可能有效地促进aaa靶向治疗。
Extracellular vesicles (EVs) are nanosized vesicles that carry cell-specific biomolecular information. Our previous studies showed that adult human bone marrow mesenchymal stem cell (BM-MSC)-derived EVs provide antiproteolytic and proregenerative effects in cultures of smooth muscle cells (SMCs) derived from an elastase-infused rat abdominal aortic aneurysm (AAA) model, and this is promising toward their use as a therapeutic platform for naturally irreversible elastic matrix aberrations in the aortic wall. Since systemically administered EVs poorly home into sites of tissue injury, disease strategies to improve their affinity toward target tissues are of great significance for EV-based treatment strategies. Toward this goal, in this work, we developed a postisolation surface modification strategy to target MSC-derived EVs to the AAA wall. The EVs were surface-conjugated with a short, synthetic, azide-modified peptide sequence for targeted binding to cathepsin K (CatK), a cysteine protease overexpressed in the AAA wall. Conjugation was performed using a copper-free click chemistry method. We determined that such conjugation improved EV uptake into cultured aneurysmal SMCs in culture and their binding to the wall of matrix injured vessels ex vivo. The proregenerative and antiproteolytic effects of MSC-EVs on cultured rat aneurysmal SMCs were also unaffected following peptide conjugation. From this study, it appears that modification with short synthetic peptide sequences seems to be an effective strategy for improving the cell-specific uptake of EVs and may be effective in facilitating AAA-targeted therapy.
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DOI：
10.1016/j.jconrel.2015.07.030
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Batrakova EV;Kim MS
通讯作者：
Kim MS
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
16
作者：
Bachurski, Daniel;Schuldner, Maximiliane;von Strandmann, Elke Pogge
通讯作者：
von Strandmann, Elke Pogge
影响因子：
4.6
作者：
Hwang, Do Won;Jo, Min Joo;Choi, Hak Soo
通讯作者：
Choi, Hak Soo
影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT