Thai Hien Bao Dieu, Kim Kyoung-Ran, Hong Kyung Tae, Voitsitskyi Taras, Lee Jun-Seok, Mao Chengde, Ahn Dae-Ro
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea.
Division of Biomedical Science and Technology, KIST School, Korea University of Science and Technology (UST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea.
ACS Cent Sci. 2020 Dec 23;6(12):2250-2258. doi: 10.1021/acscentsci.0c00763. Epub 2020 Nov 17.
A proper intracellular delivery method with target tissue specificity is critical to utilize the full potential of therapeutic molecules including siRNAs while minimizing their side effects. Herein, we prepare four small-sized DNA tetrahedrons (sTds) by self-assembly of different sugar backbone-modified oligonucleotides and screened them to develop a platform for kidney-targeted cytosolic delivery of siRNA. An biodistribution study revealed the kidney-specific accumulation of mirror DNA tetrahedron (L-sTd). Low opsonization of L-sTd in serum appeared to avoid liver clearance and keep its size small enough to be filtered through the glomerular basement membrane (GBM). After GBM filtration, L-sTd could be delivered into tubular cells by endocytosis. The kidney preference and the tubular cell uptake property of the mirror DNA nanostructure could be successfully harnessed for kidney-targeted intracellular delivery of p53 siRNA to treat acute kidney injury (AKI) in mice. Therefore, L-sTd could be a promising platform for kidney-targeted cytosolic delivery of siRNA to treat renal diseases.
一种具有靶组织特异性的合适的细胞内递送方法对于充分发挥包括小干扰RNA（siRNA）在内的治疗分子的潜力并同时将其副作用降至最低至关重要。在此，我们通过不同糖骨架修饰的寡核苷酸的自组装制备了四种小型DNA四面体（sTds），并对其进行筛选以开发一个用于将siRNA肾脏靶向胞质递送的平台。一项生物分布研究揭示了镜像DNA四面体（L-sTd）在肾脏中的特异性积累。L-sTd在血清中的低调理作用似乎避免了肝脏清除，并使其尺寸保持足够小以便通过肾小球基底膜（GBM）过滤。经过GBM过滤后，L-sTd可通过内吞作用递送至肾小管细胞。镜像DNA纳米结构的肾脏偏好性和肾小管细胞摄取特性可成功用于将p53 siRNA肾脏靶向细胞内递送，以治疗小鼠急性肾损伤（AKI）。因此，L-sTd可能是一个有前景的用于将siRNA肾脏靶向胞质递送以治疗肾脏疾病的平台。
