Liu Yang, Liu Qian, Zhang Baowen, Chen Shanshan, Shen Yanqiong, Li Zhibin, Zhang Jiachen, Yang Yi, Li Min, Wang Yucai
Department of Radiology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Nat Biomed Eng. 2025 Mar 28. doi: 10.1038/s41551-025-01373-0.
Tolerogenic antigen-presenting cells (APCs) are promising as therapeutics for suppressing T cell activation in autoimmune diseases. However, the isolation and ex vivo manipulation of autologous APCs is costly, and the process is customized for each patient. Here we show that tolerogenic APCs can be generated in vivo by delivering, via lipid nanoparticles, messenger RNA coding for the inhibitory protein programmed death ligand 1. We optimized a lipid-nanoparticle formulation to minimize its immunogenicity by reducing the molar ratio of nitrogen atoms on the ionizable lipid and the phosphate groups on the encapsulated mRNA. In mouse models of rheumatoid arthritis and ulcerative colitis, subcutaneous delivery of nanoparticles encapsulating mRNA encoding programmed death ligand 1 reduced the fraction of activated T cells, promoted the induction of regulatory T cells and effectively prevented disease progression. The method may allow for the engineering of APCs that target specific autoantigens or that integrate additional inhibitory molecules.
耐受性抗原呈递细胞（APCs）有望成为治疗自身免疫性疾病中抑制T细胞活化的疗法。然而，自体APCs的分离和体外操作成本高昂，且该过程需针对每位患者进行定制。在此，我们表明，通过脂质纳米颗粒递送编码抑制性蛋白程序性死亡配体1的信使核糖核酸（mRNA），可在体内生成耐受性APCs。我们优化了脂质纳米颗粒配方，通过降低可电离脂质上氮原子与封装mRNA上磷酸基团的摩尔比，将其免疫原性降至最低。在类风湿性关节炎和溃疡性结肠炎的小鼠模型中，皮下递送封装编码程序性死亡配体1的mRNA的纳米颗粒，可降低活化T细胞的比例，促进调节性T细胞的诱导，并有效预防疾病进展。该方法可能允许设计靶向特定自身抗原或整合其他抑制性分子的APCs。
