Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States of America.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States of America.
ACS Appl Bio Mater. 2023 May 15;6(5):1960-1969. doi: 10.1021/acsabm.3c00155. Epub 2023 Apr 11.
Wireframe DNA origami can be used to fabricate virus-like particles for a range of biomedical applications, including the delivery of nucleic acid therapeutics. However, the acute toxicity and biodistribution of these wireframe nucleic acid nanoparticles (NANPs) have not been previously characterized in animal models. In the present study, we observed no indications of toxicity in BALB/c mice following a therapeutically relevant dosage of nonmodified DNA-based NANPs via intravenous administration, based on liver and kidney histology, liver and kidney biochemistry, and body weight. Further, the immunotoxicity of these NANPs was minimal, as indicated by blood cell counts and type-I interferon and pro-inflammatory cytokines. In an SJL/J model of autoimmunity, we observed no indications of NANP-mediated DNA-specific antibody response or immune-mediated kidney pathology following the intraperitoneal administration of NANPs. Finally, biodistribution studies revealed that these NANPs accumulate in the liver within one hour, concomitant with substantial renal clearance. Our observations support the continued development of wireframe DNA-based NANPs as next-generation nucleic acid therapeutic delivery platforms.
DNA 折纸可以用于制造病毒样颗粒，用于多种生物医学应用，包括核酸治疗药物的递送。然而，这些线状核酸纳米颗粒（NANPs）在动物模型中的急性毒性和生物分布尚未得到先前的描述。在本研究中，我们观察到 BALB/c 小鼠在静脉注射治疗相关剂量的非修饰 DNA 基 NANPs 后，没有出现毒性迹象，这是基于肝和肾组织学、肝和肾功能化学以及体重得出的结论。此外，这些 NANPs 的免疫毒性很小，这可以从血细胞计数以及 I 型干扰素和促炎细胞因子得到证明。在 SJL/J 自身免疫模型中，我们观察到在腹腔内给予 NANPs 后，没有出现 NANP 介导的 DNA 特异性抗体反应或免疫介导的肾脏病理学的迹象。最后，生物分布研究表明，这些 NANPs 在一小时内积聚在肝脏中，同时伴有大量的肾脏清除。我们的观察结果支持将线状 DNA 基 NANPs 作为下一代核酸治疗药物递送平台继续开发。
