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载有大麻二酚的视网膜类器官衍生细胞外囊泡可保护遭受氧化应激的ARPE-19细胞。

Cannabidiol-Loaded Retinal Organoid-Derived Extracellular Vesicles Protect Oxidatively Stressed ARPE-19 Cells.

作者信息

Arthur Peggy, Kandoi Sangeetha, Kalvala Anil, Boirie Breana, Nathani Aakash, Aare Mounika, Bhattacharya Santanu, Kulkarni Tanmay, Sun Li, Lamba Deepak A, Li Yan, Singh Mandip

机构信息

College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.

Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA.

出版信息

Biomedicines. 2025 May 10;13(5):1167. doi: 10.3390/biomedicines13051167.

DOI:10.3390/biomedicines13051167
PMID:40426994
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12108686/
Abstract

Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness in elderly individuals aged over 50 years old. Oxidative stress plays a crucial role in the etiopathogenesis of multifactorial AMD disease. The phospholipid bilayer EVs derived from the culture-conditioned medium of human induced pluripotent stem cell (hiPSC) differentiated retinal organoids aid in cell-to-cell communication, signaling, and extracellular matrix remodeling. The goal of the current study is to establish and evaluate the encapsulation of a hydrophobic compound, cannabidiol (CBD), into retinal organoid-derived extracellular vesicles (EVs) for potential therapeutic use in AMD. hiPSC-derived retinal organoid EVs were encapsulated with CBD via sonication (CBD-EVs), and structural features were elucidated using atomic force microscopy, nanoparticle tracking analysis, and small/microRNA (miRNA) sequencing. ARPE-19 cells and oxidative-stressed (HO) ARPE-19 cells treated with CBD-EVs were assessed for cytotoxicity, apoptosis (MTT assay), reactive oxygen species (DCFDA), and antioxidant proteins (immunohistochemistry and Western blot). Distinct miRNA cargo were identified in early and late retinal organoid-derived EVs, implicating their roles in retinal development, differentiation, and functionality. The therapeutic effects of CBD-loaded EVs on oxidative-stressed ARPE-19 cells showed greater viability, decreased ROS production, downregulated expression of inflammation- and apoptosis-related proteins, and upregulated expression of antioxidants by Western blot and immunocytochemistry. miRNAs are both prognostic and predictive biomarkers and can be a target for developing therapy since they regulate RPE physiology and diseases. Our findings indicate that CBD-EVs could potentially alleviate the course of AMD by activating the targeted proteins linked to the adenosine monophosphate kinase (AMPK) pathway. Implicating the use of CBD-EVs represents a novel frontline to promote long-term abstinence from drugs and pharmacotherapy development in treating AMD.

摘要

年龄相关性黄斑变性（AMD）是50岁以上老年人不可逆失明的第三大主要原因。氧化应激在多因素AMD疾病的发病机制中起关键作用。源自人诱导多能干细胞（hiPSC）分化的视网膜类器官培养条件培养基的磷脂双层细胞外囊泡（EVs）有助于细胞间通讯、信号传导和细胞外基质重塑。本研究的目的是将一种疏水性化合物大麻二酚（CBD）封装到视网膜类器官衍生的细胞外囊泡（EVs）中，用于AMD的潜在治疗用途。通过超声处理将源自hiPSC的视网膜类器官EVs与CBD封装在一起（CBD-EVs），并使用原子力显微镜、纳米颗粒跟踪分析和小/微RNA（miRNA）测序来阐明其结构特征。对用CBD-EVs处理的ARPE-19细胞和氧化应激（HO）ARPE-19细胞进行细胞毒性、凋亡（MTT试验）、活性氧（DCFDA）和抗氧化蛋白（免疫组织化学和蛋白质印迹）评估。在早期和晚期视网膜类器官衍生的EVs中鉴定出不同的miRNA货物，暗示它们在视网膜发育、分化和功能中的作用。负载CBD的EVs对氧化应激ARPE-19细胞的治疗效果通过蛋白质印迹和免疫细胞化学显示出更高的活力、降低的ROS产生、炎症和凋亡相关蛋白表达下调以及抗氧化剂表达上调。miRNA既是预后性又是预测性生物标志物，并且由于它们调节视网膜色素上皮（RPE）生理学和疾病，因此可以成为开发治疗方法的靶点。我们的研究结果表明，CBD-EVs可能通过激活与腺苷单磷酸激酶（AMPK）途径相关的靶向蛋白来缓解AMD的病程。这意味着使用CBD-EVs代表了在治疗AMD中促进长期戒毒和药物治疗开发的新前沿。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a6/12108686/8eea1abe2353/biomedicines-13-01167-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a6/12108686/33539a696c6f/biomedicines-13-01167-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a6/12108686/3ebe786f165e/biomedicines-13-01167-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a6/12108686/e3bbfb408951/biomedicines-13-01167-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22a6/12108686/8eea1abe2353/biomedicines-13-01167-g006.jpg

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