细胞外囊泡作为基于 CRISPR-Cas 的上皮性卵巢癌治疗的潜在递送平台。
Extracellular vesicles as a potential delivery platform for CRISPR-Cas based therapy in epithelial ovarian cancer.
发表日期:2023 Oct 10
作者:
Nihar Godbole, Alexander Quinn, Flavio Carrion, Emanuele Pelosi, Carlos Salomon
来源:
SEMINARS IN CANCER BIOLOGY
摘要:
卵巢癌(OC)是最常见的妇科恶性肿瘤,也是全球女性中第八大诊断癌症。目前,它是全球患者癌症相关死亡的第五大原因。全球 OC 致死率的主要因素包括延迟诊断、化疗耐药、高转移率和亚型的异质性。尽管不断努力开发新型靶向疗法和化疗药物,但 OC 耐药和复发的挑战仍然存在。在过去的十年中,基于 CRISPR-Cas 的基因组编辑已成为修改遗传和表观遗传机制的强大工具,具有治疗多种疾病的潜力。然而,CRISPR-Cas技术的治疗应用面临的一个重大挑战是缺乏将CRISPR分子机制传递到靶细胞或组织中的最佳载体。最近,细胞外囊泡(EV)作为各种治疗剂的潜在递送载体而受到关注。几乎所有细胞都会将这些异质的膜衍生囊泡释放到细胞外空间。它们在管腔内携带蛋白质和核酸的分子货物,并被富含胆固醇的磷脂双层膜包裹。电动汽车通过向邻近和远处的细胞运送货物来积极参与细胞间的通信。它们具有保护分子货物免遭降解和跨越生物屏障的固有能力,这使它们成为将 CRISPR-Cas 核糖核蛋白 (RNP) 递送至靶细胞的理想选择。此外,与腺相关病毒、慢病毒和合成纳米粒子等经典递送平台相比,它们表现出更高的生物相容性、更低的免疫原性和更低的毒性。本综述探讨了采用不同 CRISPR-Cas 系统靶向 OC 中特定基因的潜力,同时还讨论了工程 EV 加载 CRISPR 组件并增强其靶向能力的各种方法。版权所有 © 2023。由 Elsevier Ltd 出版。
Ovarian Cancer (OC) is the most common gynecological malignancy and the eighth most diagnosed cancer in females worldwide. Presently, it ranks as the fifth leading cause of cancer-related mortality among patients globally. Major factors contributing to the lethality of OC worldwide include delayed diagnosis, chemotherapy resistance, high metastatic rates, and the heterogeneity of subtypes. Despite continuous efforts to develop novel targeted therapies and chemotherapeutic agents, challenges persist in the form of OC resistance and recurrence. In the last decade, CRISPR-Cas-based genome editing has emerged as a powerful tool for modifying genetic and epigenetic mechanisms, holding potential for treating numerous diseases. However, a significant challenge for therapeutic applications of CRISPR-Cas technology is the absence of an optimal vehicle for delivering CRISPR molecular machinery into targeted cells or tissues. Recently, extracellular vesicles (EVs) have gained traction as potential delivery vehicles for various therapeutic agents. These heterogeneous, membrane-derived vesicles are released by nearly all cells into extracellular spaces. They carry a molecular cargo of proteins and nucleic acids within their intraluminal space, encased by a cholesterol-rich phospholipid bilayer membrane. EVs actively engage in cell-to-cell communication by delivering cargo to both neighboring and distant cells. Their inherent ability to shield molecular cargo from degradation and cross biological barriers positions them ideally for delivering CRISPR-Cas ribonucleoproteins (RNP) to target cells. Furthermore, they exhibit higher biocompatibility, lower immunogenicity, and reduced toxicity compared to classical delivery platforms such as adeno-associated virus, lentiviruses, and synthetic nanoparticles. This review explores the potential of employing different CRISPR-Cas systems to target specific genes in OC, while also discussing various methods for engineering EVs to load CRISPR components and enhance their targeting capabilities.Copyright © 2023. Published by Elsevier Ltd.