Han Sangwoo, Yoo Woojung, Carton Olivia, Joo Jinmyoung, Kwon Ester J
Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
Small. 2025 Mar;21(10):e2405806. doi: 10.1002/smll.202405806. Epub 2024 Nov 5.
Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long-term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub-100 nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT-based RNA particles, in this method, sub-100 nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG-RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half-life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF-α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub-100 nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI.
创伤性脑损伤（TBI）在全球范围内影响着数百万人，然而目前尚无经批准的可解决长期脑健康问题的疗法。为了创建一种与全身给药后TBI中的小干扰RNA（siRNA）递送相关的技术，合成并分离出具有滚环转录（RCT）的亚100纳米纳米颗粒，以提高有效载荷向受伤大脑的递送。与基于传统RCT的RNA颗粒不同，在该方法中，分离出亚100纳米RNA纳米颗粒（RNP）。为了增强RNP的药代动力学，合成带有修饰碱基的RNP，以便将聚乙二醇（PEG）接枝到RNP上。聚乙二醇化RNP（PEG-RNP）在体外不会显著影响其敲低活性，并且在全身给药后导致更长的血液半衰期，并在TBI小鼠模型中更多地积聚到受伤大脑中。为了证明RNP的RNA干扰（RNAi）活性，在TBI小鼠模型中全身给药RNP后，证明了受伤脑组织中炎性细胞因子肿瘤坏死因子-α（TNF-α）的敲低。总之，合成并分离出亚100纳米的小多聚体RNA纳米颗粒，其可以使用易操作的化学方法进行修饰，以创建一种适用于TBI全身RNAi治疗的技术。
