湖南大学蒋健晖团队报道了诱导型核糖核酸酶靶向嵌合体沉默G-Quadruplex mRNAs用于精确肿瘤治疗。相关研究成果于2024年6月4日发表于国际顶尖学术期刊《美国化学会杂志》。

核糖核酸酶靶向嵌合体（RIBOTAC）是一种新兴的靶向治疗策略。然而，通过生物正交或细胞特异性触发器选择性激活的RIBOTAC尚未被探索。

该文中，研究人员开发了一种诱导型RIBOTAC（iRIBOTAC）策略，该策略能够按需降解G-quadruplex（G4）RNA，用于精确的癌症治疗。iRIBOTAC是通过将RNA G4结合物与笼状核糖核酸酶募集物偶联而设计的，该募集物可以通过生物正交反应、肿瘤特异性酶或代谢产物进行衰变。通过将近红外（NIR）荧光G4配体与非竞争性G4配体偶联，以协同增强的亲和力赋予结合G4s荧光活化，来设计二价G4粘合剂。

iRIBOTAC被证明在生物正交或细胞特异性刺激下激活时可大大敲低G4 RNA，RNA测序揭示了涉及细胞杀伤、通道调节活性和代谢的基因表达失调。这种策略还显示出对细胞命运的关键影响，具有显著的细胞凋亡的生化特征。小鼠模型研究表明，iRIBOTAC可以通过生物正交和肿瘤特异性对照，对肿瘤进行选择性成像和生长抑制，突出了G4RNA靶向和诱导性沉默是癌症治疗的一种有价值的RIBOTAC范式。

附：英文原文

Title: G-Quadruplex mRNAs Silencing with Inducible Ribonuclease Targeting Chimera for Precision Tumor Therapy

Author: Yuan Zhang, Lingyan Wang, Fenglin Wang, Xia Chu, Jian-Hui Jiang

Issue&Volume: June 4, 2024

Abstract: Ribonuclease targeting chimera (RIBOTAC) represents an emerging strategy for targeted therapy. However, RIBOTAC that is selectively activated by bio-orthogonal or cell-specific triggers has not been explored. We developed a strategy of inducible RIBOTAC (iRIBOTAC) that enables on-demand degradation of G-quadruplex (G4) RNAs for precision cancer therapy. iRIBOTAC is designed by coupling an RNA G4 binder with a caged ribonuclease recruiter, which can be decaged by a bio-orthogonal reaction, tumor-specific enzyme, or metabolite. A bivalent G4 binder is engineered by conjugating a near-infrared (NIR) fluorescence G4 ligand to a noncompetitive G4 ligand, conferring fluorescence activation on binding G4s with synergistically enhanced affinity. iRIBOTAC is demonstrated to greatly knockdown G4 RNAs upon activation under bio-orthogonal or cell-specific stimulus, with dysregulation of gene expressions involving cell killing, channel regulator activity, and metabolism as revealed by RNA sequencing. This strategy also shows a crucial effect on cell fate with remarkable biochemical hallmarks of apoptosis. Mice model studies demonstrate that iRIBOTAC allows selective imaging and growth suppression of tumors with bio-orthogonal and tumor-specific controls, highlighting G4 RNA targeting and inducible silencing as a valuable RIBOTAC paradigm for cancer therapy.

DOI: 10.1021/jacs.4c02091

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c02091