Münter Rasmus, Christensen Esben, Andresen Thomas L, Larsen Jannik B
Biotherapeutic Engineering and Drug Targeting, Department of Health Technology, Technical University of Denmark (DTU), 2800 Kongens Lyngby, Denmark.
Mol Ther Methods Clin Dev. 2023 May 11;29:450-459. doi: 10.1016/j.omtm.2023.05.008. eCollection 2023 Jun 8.
Following the recent approval of both siRNA- and mRNA-based therapeutics, nucleic acid therapies are considered a game changer in medicine. Their envisioned widespread use for many therapeutic applications with an array of cellular target sites means that various administration routes will be employed. Concerns exist regarding adverse reactions against the lipid nanoparticles (LNPs) used for mRNA delivery, as PEG coatings on nanoparticles can induce severe antibody-mediated immune reactions, potentially being boosted by the inherently immunogenic nucleic acid cargo. While exhaustive information is available on how physicochemical features of nanoparticles affects immunogenicity, it remains unexplored how the fundamental choice of administration route regulates anti-particle immunity. Here, we directly compared antibody generation against PEGylated mRNA-carrying LNPs administered by the intravenous, intramuscular, or subcutaneous route, using a novel sophisticated assay capable of measuring antibody binding to authentic LNP surfaces with single-particle resolution. Intramuscular injections in mice were found to generate overall low and dose-independent levels of anti-LNP antibodies, while both intravenous and subcutaneous LNP injections generated substantial and highly dose-dependent levels. These findings demonstrate that before LNP-based mRNA medicines can be safely applied to new therapeutic applications, it will be crucial to carefully consider the choice of administration route.
随着基于小干扰RNA（siRNA）和信使核糖核酸（mRNA）的疗法近期获得批准，核酸疗法被视为医学领域的变革者。它们有望广泛应用于众多具有一系列细胞靶点的治疗应用，这意味着将采用多种给药途径。人们对用于mRNA递送的脂质纳米颗粒（LNP）的不良反应存在担忧，因为纳米颗粒上的聚乙二醇（PEG）涂层可引发严重的抗体介导免疫反应，而具有内在免疫原性的核酸载荷可能会加剧这种反应。虽然关于纳米颗粒的物理化学特性如何影响免疫原性已有详尽信息，但给药途径的基本选择如何调节抗颗粒免疫仍未得到探索。在此，我们使用一种能够以单颗粒分辨率测量抗体与真实LNP表面结合的新型精密检测方法，直接比较了通过静脉内、肌肉内或皮下途径给药的携带PEG化mRNA的LNP所引发的抗体生成情况。结果发现，小鼠肌肉内注射产生的抗LNP抗体总体水平较低且与剂量无关，而静脉内和皮下LNP注射均产生了大量且高度依赖剂量的抗体水平。这些发现表明，在基于LNP的mRNA药物能够安全应用于新的治疗应用之前，仔细考虑给药途径的选择至关重要。
