Abe Shunji, Takata Haruka, Shimizu Taro, Kawaguchi Yoshino, Fukuda Shoichiro, Yamamoto Haruka, Ando Hidenori, Ishida Tatsuhiro
Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan; Innovative Research Center for Drug Delivery System, Institute of Biomedical Sciences, Tokushima University, 770-8505 Tokushima, Japan.
J Control Release. 2025 Jul 10;383:113821. doi: 10.1016/j.jconrel.2025.113821. Epub 2025 May 9.
With the approval of mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lipid nanoparticles (LNP) have emerged as a powerful tool for nucleic acid delivery. Modification of LNP with polyethylene glycol (PEG)-lipids contributes to their in vitro and in vivo stability by reducing aggregation of the particles. Despite the general acknowledgement of the low immunogenicity of PEG, there are numerous reports of the occurrence of anti-PEG antibodies in the blood of healthy individuals. Furthermore, there are reports that pre-existing anti-PEG IgM antibodies attenuated the efficacy of PEG-modified drugs administered systemically. Skeletal muscles, the administration site for mRNA vaccines, are highly vascularized by a network of blood vessels to provide them with nutrients and oxygen. Since skeletal muscles can contain circulating anti-PEG antibodies or the administered mRNA-LNP extravasate into bloodstream, the purpose of this study was to evaluate the effects of pre-existing anti-PEG IgM on the protein translation, biodistribution, and humoral responses to mRNA-loaded LNP (mRNA-LNP) administered intramuscularly (i.m.) in mice. We found that the presence of anti-PEG IgM in blood has only a minor effect on the translation and distribution of mRNA-LNP in the localized muscle area where the mRNA-LNP were administered. Circulating anti-PEG IgM did not increase the total accumulation of mRNA-LNP in the liver, but did markedly diminish its protein translation because the mRNA-LNP were delivered primarily to Kupffer cells rather than to hepatocytes. Binding of anti-PEG IgM to mRNA-LNP, and subsequent complement activation, suppressed mRNA translation loaded in LNP in the liver. Repeated intramuscular injections of SARS-CoV-2 Spike protein mRNA-LNP elicited a robust immune response. Our results indicate that the presence of circulating anti-PEG IgM does not interfere with the efficiency of mRNA vaccines administered i.m. in mice. We can speculate that non-specific translation of mRNA vaccines in somatic cells may be inhibited in vivo by circulating anti-PEG IgM, reducing adverse effects such as hepatitis and myocarditis that are caused by immune responses against translated antigen proteins.
随着严重急性呼吸综合征冠状病毒2（SARS-CoV-2）信使核糖核酸（mRNA）疫苗的获批，脂质纳米颗粒（LNP）已成为一种强大的核酸递送工具。用聚乙二醇（PEG）-脂质修饰LNP可通过减少颗粒聚集来提高其在体外和体内的稳定性。尽管人们普遍认为PEG的免疫原性较低，但有大量报道称健康个体血液中会出现抗PEG抗体。此外，有报道称预先存在的抗PEG IgM抗体会减弱全身给药的PEG修饰药物的疗效。骨骼肌是mRNA疫苗的给药部位，由血管网络高度血管化，为其提供营养和氧气。由于骨骼肌可能含有循环抗PEG抗体，或者给药的mRNA-LNP会渗入血液，因此本研究的目的是评估预先存在的抗PEG IgM对小鼠肌肉注射（i.m.）负载mRNA的LNP（mRNA-LNP）的蛋白质翻译、生物分布和体液反应的影响。我们发现，血液中抗PEG IgM的存在对mRNA-LNP在给药局部肌肉区域的翻译和分布只有轻微影响。循环抗PEG IgM并未增加mRNA-LNP在肝脏中的总积累，但确实显著降低了其蛋白质翻译，因为mRNA-LNP主要递送至库普弗细胞而非肝细胞。抗PEG IgM与mRNA-LNP的结合以及随后的补体激活抑制了肝脏中LNP负载的mRNA的翻译。重复肌肉注射SARS-CoV-2刺突蛋白mRNA-LNP可引发强烈的免疫反应。我们的结果表明，循环抗PEG IgM的存在不会干扰小鼠肌肉注射mRNA疫苗的效率。我们可以推测，循环抗PEG IgM可能在体内抑制了体细胞中mRNA疫苗的非特异性翻译，减少了由针对翻译抗原蛋白的免疫反应引起的肝炎和心肌炎等不良反应。
