School of Chemistry and Chemical Engineering, New Cornerstone Science Laboratory, Frontiers Science Center for Transformative Molecules, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
School of Molecular Sciences and Biodesign Center for Molecular Design and Biomimetics, Biodesign Institute, Arizona State University, Tempe, Arizona 85287, United States.
J Am Chem Soc. 2023 Aug 9;145(31):17112-17124. doi: 10.1021/jacs.3c03477. Epub 2023 Jul 27.
Ligands targeting nucleic acid-sensing receptors activate the innate immune system and play a critical role in antiviral and antitumoral therapy. However, ligand design for stability, targeted delivery, and predictive immunogenicity is largely hampered by the sophisticated mechanism of the nucleic acid-sensing process. Here, we utilize single-stranded RNA (ssRNA) origami with precise structural designability as nucleic acid sensor-based ligands to achieve improved biostability, organelle-level targeting, and predictive immunogenicity. The natural ssRNAs self-fold into compact nanoparticles with defined shapes and morphologies and exhibit resistance against RNase digestion and prolonged retention in macrophage endolysosomes. We find that programming the edge length of ssRNA origami can precisely regulate the degree of macrophage activation a toll-like receptor-dependent pathway. Further, we demonstrate that the ssRNA origami-based ligand elicits an anti-tumoral immune response of macrophages and neutrophils in the tumor microenvironment and retards tumor growth in the mouse pancreatic tumor model. Our ssRNA origami strategy utilizes structured RNA ligands to achieve predictive immune activation, providing a new solution for nucleic acid sensor-based ligand design and biomedical applications.
靶向核酸传感受体的配体激活先天免疫系统，在抗病毒和抗肿瘤治疗中发挥着关键作用。然而，由于核酸传感过程的复杂机制，配体的设计在稳定性、靶向递送和预测免疫原性方面受到了很大的阻碍。在这里，我们利用具有精确结构设计能力的单链 RNA（ssRNA）折纸作为基于核酸传感器的配体，以提高生物稳定性、细胞器水平靶向和预测免疫原性。天然 ssRNA 可以自我折叠成具有确定形状和形态的紧凑纳米颗粒，并且对核糖核酸酶的消化具有抗性，并且在巨噬细胞内溶酶体中的保留时间延长。我们发现，对 ssRNA 折纸的边长进行编程可以精确调节巨噬细胞激活的程度——这是一个 Toll 样受体依赖性途径。此外，我们证明了基于 ssRNA 折纸的配体在肿瘤微环境中引发巨噬细胞和中性粒细胞的抗肿瘤免疫反应，并延缓小鼠胰腺肿瘤模型中的肿瘤生长。我们的 ssRNA 折纸策略利用结构 RNA 配体来实现预测性免疫激活，为基于核酸传感器的配体设计和生物医学应用提供了新的解决方案。
