Abstract：
Acute lung injury (ALI) is an acute inflammatory process that can result in life-threatening consequences. Programmable DNA nanostructures have emerged as excellent nanoplatforms for microRNA-based therapeutics, offering potential nanomedicines for ALI treatment. Nonetheless, the traditional systematic administration of nanomedicines is constrained by low delivery efficiency, poor pharmacokinetics, and nonspecific side effects. Here, we identify macrophage microRNA-155 as a novel therapeutic target using the magnetic bead sorting technique. We further construct a DNA nanotubular nucleic acid drug antagonizing microRNA-155 (NT-155) for ALI treatment through intratracheal administration. Flow cytometry results demonstrate that NT-155, when inhaled, is taken up much more effectively by macrophages and dendritic cells in the bronchoalveolar lavage fluid of ALI mice. Furthermore, NT-155 effectively silences the overexpressed microRNA-155 in macrophages and exerts excellent inflammation inhibition effects in vitro and ALI mouse models. Mechanistically, NT-155 suppresses microRNA-155 expression and activates its target gene SOCS1, inhibiting the p-P65 signaling pathway and suppressing proinflammatory cytokine secretion. The current study suggests that deliberately designed nucleic acid drugs are promising nanomedicines for ALI treatment and the local administration may open up new practical applications of DNA in the future.
摘要：
急性肺损伤（ALI）是一种急性炎症过程，可导致危及生命的后果。可编程DNA纳米结构已经成为基于microRNA的治疗的优秀纳米平台。为ALI治疗提供潜在的纳米药物。尽管如此，纳米药物的传统系统给药受到低递送效率的限制，不良的药代动力学，和非特异性副作用。这里,我们使用磁珠分选技术将巨噬细胞microRNA-155鉴定为新的治疗靶标。我们通过气管内给药进一步构建了用于ALI治疗的拮抗microRNA-155（NT-155）的DNA纳米管核酸药物。流式细胞术结果表明，NT-155吸入后，ALI小鼠的支气管肺泡灌洗液中的巨噬细胞和树突状细胞更有效地吸收。此外，NT-155可有效沉默巨噬细胞中过表达的microRNA-155，并在体外和ALI小鼠模型中发挥出色的炎症抑制作用。机械上,NT-155抑制microRNA-155表达并激活其靶基因SOCS1，抑制p-P65信号通路并抑制促炎细胞因子分泌。目前的研究表明，故意设计的核酸药物是ALI治疗的有前途的纳米药物，局部给药可能在未来开辟DNA的新的实际应用。
