mRNA-Lipid nanoparticles (LNPs) are at the forefront of global medical research. With the development of mRNA-LNP vaccines to combat the COVID-19 pandemic, the clinical potential of this platform was unleashed. Upon administering 16 billion doses that protected billions of people, it became clear that a fraction of them witnessed mild and in some cases even severe adverse effects. Therefore, it is paramount to define the safety along with the therapeutic efficacy of the mRNA-LNP platform for the successful translation of new genetic medicines based on this technology. While mRNA was the effector molecule of this platform, the ionizable lipid component of the LNPs played an indispensable role in its success. However, both of these components possess the ability to induce undesired immunostimulation, which is an area that needs to be addressed systematically. The immune cell agitation caused by this platform is a two-edged sword as it may prove beneficial for vaccination but detrimental to other applications. Therefore, a key challenge in advancing the mRNA-LNP drug delivery platform from bench to bedside is understanding the immunostimulatory behavior of these components. Herein, we provide a detailed overview of the structural modifications and immunogenicity of synthetic mRNA. We discuss the effect of ionizable lipid structure on LNP functionality and offer a mechanistic overview of the ability of LNPs to elicit an immune response. Finally, we shed some light on the current status of this technology in clinical trials and discuss a few challenges to be addressed to advance the field.

mRNA-脂质纳米粒子（LNP）处于全球医学研究的前沿。随着用于对抗 COVID-19 大流行的 mRNA-LNP 疫苗的开发，该平台的临床潜力被释放出来。在注射了 160 亿剂疫苗并保护了数十亿人之后，很明显，其中一小部分人出现了轻微的不良反应，在某些情况下甚至出现了严重的不良反应。因此，为了成功转化基于该技术的新基因药物，确定 mRNA-LNP 平台的安全性和治疗功效至关重要。虽然 mRNA 是该平台的效应分子，但 LNP 的可电离脂质成分在其成功中发挥了不可或缺的作用。然而，这两种成分都具有诱导不良免疫刺激的能力，这是一个需要系统解决的领域。该平台引起的免疫细胞扰动是一把双刃剑，因为它可能对疫苗接种有利，但对其他应用不利。因此，将 mRNA-LNP 药物递送平台从实验室推进到临床的一个关键挑战是了解这些成分的免疫刺激行为。在此，我们详细概述了合成 mRNA 的结构修饰和免疫原性。我们讨论了可电离脂质结构对 LNP 功能的影响，并提供了 LNP 引发免疫反应能力的机制概述。最后，我们阐明了该技术在临床试验中的现状，并讨论了推进该领域需要解决的一些挑战。