Therapeutic potential of urinary extracellular vesicles in delivering functional proteins and modulating gene expression for genetic kidney disease

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2025-03-26 DOI:10.1016/j.biomaterials.2025.123296

Yi Huang , Ali Osouli , Hui Li , Megan Dudaney , Jessica Pham , Valeria Mancino , Taranatee Khan , Baishali Chaudhuri , Nuria M. Pastor-Soler , Kenneth R. Hallows , Eun Ji Chung

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Abstract

Chronic kidney disease (CKD) is a widespread health concern, impacting approximately 600 million individuals worldwide and marked by a progressive decline in kidney function. A common form of CKD is autosomal dominant polycystic kidney disease (ADPKD), which is the most inherited genetic kidney disease and affects greater than 12.5 million individuals globally. Given that there are over 400 pathogenic PKD1/PKD2 mutations in patients with ADPKD, relying solely on small molecule drugs targeting a single signaling pathway has not been effective in treating ADPKD. Urinary extracellular vesicles (uEVs) are naturally released by cells from the kidneys and the urinary tract, and uEVs isolated from non-disease sources have been reported to carry functional polycystin-1 (PC1) and polycystin-2 (PC2), the respective products of PKD1 and PKD2 genes that are mutated in ADPKD. uEVs from non-disease sources, as a result, have the potential to provide a direct solution to the root of the disease by delivering functional proteins that are mutated in ADPKD. To test our hypothesis, we first isolated uEVs from healthy mice urine and conducted a comprehensive characterization of uEVs. Then, PC1 levels and EV markers CD63 and TSG101 of uEVs were confirmed via ELISA and Western blot. Following characterization of uEVs, the in vitro cellular uptake, inhibition of cyst growth, and gene rescue ability of uEVs were demonstrated in kidney cells. Next, upon administration of uEVs in vivo, uEVs showed bioavailability and accumulation in the kidneys. Lastly, uEV treatment in ADPKD mice (Pkd1^fl/fl;Pax8-rtTA;Tet-O-Cre) showed smaller kidney size, lower cyst index, and enhanced PC1 levels without affecting safety despite repeated treatment. In summary, we demonstrate the potential of uEVs as natural nanoparticles to deliver protein and gene therapies for the treatment of chronic and genetic kidney diseases such as ADPKD.

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尿细胞外囊泡在遗传性肾病中传递功能蛋白和调节基因表达的治疗潜力

慢性肾脏疾病（CKD）是一个广泛关注的健康问题，影响着全球约6亿人，其特征是肾功能的进行性下降。CKD的一种常见形式是常染色体显性多囊肾病（ADPKD），这是最遗传性的遗传性肾脏疾病，影响全球超过1250万人。鉴于ADPKD患者中存在400多种致病性PKD1/PKD2突变，仅依靠靶向单一信号通路的小分子药物治疗ADPKD并不有效。尿细胞外囊泡（uEVs）由肾脏和尿路的细胞自然释放，据报道，从非疾病来源分离的uEVs携带功能性多囊蛋白-1 （PC1）和多囊蛋白-2 (PC2)，它们分别是PKD1和PKD2基因的产物，在ADPKD中发生突变。因此，来自非疾病来源的uev有可能通过递送在ADPKD中发生突变的功能蛋白，为疾病的根源提供直接解决方案。为了验证我们的假设，我们首先从健康小鼠尿液中分离出uev，并对uev进行了全面的表征。然后通过ELISA和Western blot检测evs的PC1水平和evs标志物CD63、TSG101。在对uev进行表征后，在肾细胞中证实了uev的体外细胞摄取、抑制囊肿生长和基因拯救能力。接下来，在体内给药后，uev显示出在肾脏中的生物利用度和蓄积。最后，uEV治疗ADPKD小鼠（Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre）的肾脏尺寸变小，囊肿指数降低，PC1水平升高，尽管反复治疗，但不影响安全性。总之，我们证明了uev作为天然纳米颗粒在慢性和遗传性肾脏疾病（如ADPKD）的治疗中提供蛋白质和基因疗法的潜力。

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来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.