使用 DNA 折纸技术对 TRAIL 三聚体进行纳米级组织以促进死亡受体聚集和癌细胞凋亡,Small

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使用 DNA 折纸技术对 TRAIL 三聚体进行纳米级组织以促进死亡受体聚集和癌细胞凋亡
Small ( IF 13.0 ) Pub Date : 2023-03-08 , DOI: 10.1002/smll.202206160
Nana Ma ₁ , Keman Cheng ₁ , Qingqing Feng ₁ , Guangna Liu ₁ , Jie Liang ₁ , Xiaotu Ma ₁ , Zhiqiang Chen ₁ , Yichao Lu ₁ , Xinwei Wang ₁ , Wei He ₂ , Hu Xu ₂ , Shan Wu ₂ , Jiajia Zou ₃ , Quanwei Shi ₃ , Guangjun Nie _{1,

4} , Xiao Zhao _{1,

4,

5}

Affiliation

通过诱导死亡受体 (DR) 聚集激活下游信号，肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 三聚体触发肿瘤细胞凋亡。然而，当前基于 TRAIL 的疗法的不良激动活性限制了它们的抗肿瘤效率。TRAIL 三聚体在不同配体间距离的纳米级空间组织仍然具有挑战性，这对于理解 TRAIL 和 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，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，形成 DNA-TRAIL3 三聚体（DNA origami with surface decoration of three TRAIL monomers ). 凭借 DNA 折纸的空间可寻址性，配体间距离精确控制在 15 到 60 nm 之间。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≈40 nm 是 DNA-TRAIL3 三聚体诱导死亡受体聚集并导致细胞凋亡的临界配体间距离。单元”模型被提出用于由 DNA-TRAIL3 三聚体诱导的 DR5 聚类。

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Nanoscale Organization of TRAIL Trimers using DNA Origami to Promote Clustering of Death Receptor and Cancer Cell Apoptosis

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.

更新日期：2023-03-08

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