CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, 11 Beiyitiao, Zhongguancun, Beijing, 100190, China.
State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China.
Small. 2023 Jun;19(23):e2206160. doi: 10.1002/smll.202206160. Epub 2023 Mar 8.
Through inducing death receptor (DR) clustering to activate downstream signaling, tumor necrosis factor related apoptosis inducing ligand (TRAIL) trimers trigger apoptosis of tumor cells. However, the poor agonistic activity of current TRAIL-based therapeutics limits their antitumor efficiency. The nanoscale spatial organization of TRAIL trimers at different interligand distances is still challenging, which is essential for the understanding of interaction pattern between TRAIL and DR. In this study, a flat rectangular DNA origami is employed as display scaffold, and an "engraving-printing" strategy is developed to rapidly decorate three TRAIL monomers onto its surface to form DNA-TRAIL3 trimer (DNA origami with surface decoration of three TRAIL monomers). With the spatial addressability of DNA origami, the interligand distances are precisely controlled from 15 to 60 nm. Through comparing the receptor affinity, agonistic activity and cytotoxicity of these DNA-TRAIL3 trimers, it is found that ≈40 nm is the critical interligand distance of DNA-TRAIL3 trimers to induce death receptor clustering and the resulting apoptosis.Finally, a hypothetical "active unit" model is proposed for the DR5 clustering induced by DNA-TRAIL3 trimers.
通过诱导死亡受体 (DR) 聚集来激活下游信号，肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 三聚体引发肿瘤细胞凋亡。然而，目前基于 TRAIL 的治疗方法的激动活性差限制了它们的抗肿瘤效率。不同配体间距离的 TRAIL 三聚体的纳米级空间组织仍然具有挑战性，这对于理解 TRAIL 与 DR 之间的相互作用模式至关重要。在这项研究中，采用平面矩形 DNA 折纸作为展示支架，并开发了一种“雕刻印刷”策略，将三个 TRAIL 单体快速装饰到其表面上，以形成 DNA-TRAIL3 三聚体（表面装饰有三个 TRAIL 单体的 DNA 折纸）。通过 DNA 折纸的空间可寻址性，可以精确控制配体间距离从 15 到 60nm。通过比较这些 DNA-TRAIL3 三聚体的受体亲和力、激动活性和细胞毒性，发现 ≈40nm 是 DNA-TRAIL3 三聚体诱导死亡受体聚集和导致凋亡的关键配体间距离。最后，提出了一个假设的“活性单位”模型，用于 DNA-TRAIL3 三聚体诱导的 DR5 聚集。
