Zwolsman Robby, Darwish Youssef B, Kluza Ewelina, van der Meel Roy
Laboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2025 Mar-Apr;17(2):e70007. doi: 10.1002/wnan.70007.
Over the last decades, messenger RNA (mRNA) has emerged as a promising therapeutic modality, enabling the delivery of genetic instructions to cells for producing therapeutic proteins or antigens. As such, mRNA-based therapies can be developed for a wide range of conditions, including infections, cancer, metabolic disorders, and genetic diseases. Nevertheless, using mRNA therapeutically requires chemical modifications to reduce immunostimulatory effects and nanotechnology to prevent degradation and ensure intracellular delivery. Lipid nanoparticles (LNPs) have become the most effective delivery platform for mRNA therapeutics, which are primarily employed for vaccine purposes following local administration and hepatic applications following systemic administration. Here, we review the state-of-the-art LNP-mRNA technology and discuss its potential for immunotherapy. We first outline the requirements for mRNA to be used therapeutically, including the role of LNP-mediated delivery. Next, we highlight LNP-mRNA immunotherapy approaches for vaccination, immuno-oncology, and autoimmune disorders. In addition, we discuss challenges that are limiting LNP-mRNA's widespread use, including tunable biodistribution and immunostimulatory effects. Finally, we provide an outlook on how implementing approaches such as library screening and machine learning will guide the development of next-generation mRNA therapeutics.
在过去几十年里，信使核糖核酸（mRNA）已成为一种很有前景的治疗方式，能够将遗传指令传递给细胞以产生治疗性蛋白质或抗原。因此，可以针对包括感染、癌症、代谢紊乱和遗传疾病在内的多种病症开发基于mRNA的疗法。然而，将mRNA用于治疗需要进行化学修饰以降低免疫刺激作用，并利用纳米技术防止其降解并确保细胞内递送。脂质纳米颗粒（LNP）已成为mRNA疗法最有效的递送平台，局部给药后主要用于疫苗用途，全身给药后用于肝脏应用。在此，我们综述了最先进的LNP-mRNA技术，并讨论其在免疫治疗方面的潜力。我们首先概述治疗性使用mRNA的要求，包括LNP介导递送的作用。接下来，我们重点介绍LNP-mRNA在疫苗接种、免疫肿瘤学和自身免疫性疾病方面的免疫治疗方法。此外，我们讨论了限制LNP-mRNA广泛应用的挑战，包括可调节的生物分布和免疫刺激作用。最后，我们展望了实施文库筛选和机器学习等方法将如何指导下一代mRNA疗法的开发。
