National Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Nanjing Road 106, Qingdao 266071, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Wenhaizhong Road 168, Qingdao 266237, China.
College of Marine Life Science, Ocean University of China, Yushan Road 5, Qingdao 266003, China.
J Control Release. 2023 Nov;363:275-289. doi: 10.1016/j.jconrel.2023.09.027. Epub 2023 Sep 28.
Exosomes are endosome-derived extracellular vesicles about 100 nm in diameter. They are emerging as promising delivery platforms due to their advantages in biocompatibility and engineerability. However, research into and applications for engineered exosomes are still limited to a few areas of medicine in mammals. Here, we expanded the scope of their applications to sex-determining gene studies in early vertebrates. An integrated strategy for constructing the exosome-based delivery system was developed for efficient regulation of dmrt1, which is one of the most widely used sex-determining genes in metazoans. By combining classical methods in molecular biology and the latest technology in bioinformatics, isomiR-124a was identified as a dmrt1 inhibitor and was loaded into exosomes and a testis-targeting peptide was used to modify exosomal surface for efficient delivery. Results showed that isomiR-124a was efficiently delivered to the testes by engineered exosomes and revealed that dmrt1 played important roles in maintaining the regular structure and function of testis in juvenile fish. This is the first de novo development of an exosome-based delivery system applied in the study of sex-determining gene, which indicates an attractive prospect for the future applications of engineered exosomes in exploring more extensive biological conundrums.
外泌体是直径约 100nm 的内体衍生的细胞外囊泡。由于其具有生物相容性和工程改造性的优势，它们正在成为有前途的递药平台。然而，工程化外泌体的研究和应用仍然局限于哺乳动物的几个医学领域。在这里，我们将其应用范围扩展到早期脊椎动物性别决定基因研究领域。开发了一种基于外泌体的递药系统的综合构建策略，以高效调控 dmrt1，dmrt1 是后生动物中最广泛使用的性别决定基因之一。通过结合分子生物学的经典方法和生物信息学的最新技术，鉴定出 isomiR-124a 是 dmrt1 的抑制剂，并将其载入外泌体中，使用睾丸靶向肽对其表面进行修饰，以实现高效递药。结果表明，工程化外泌体可有效递送到睾丸，并且表明 dmrt1 在维持幼鱼睾丸的正常结构和功能方面发挥着重要作用。这是首次在性别决定基因研究中应用基于外泌体的递药系统，这为未来工程化外泌体在探索更广泛的生物学难题中的应用提供了有吸引力的前景。
