Ru(II)络合物介导的相分离放大光催化RNA损伤以刺激RIG - I免疫治疗。

IF 8.7 Q1 CHEMISTRY, MULTIDISCIPLINARY
JACS Au Pub Date : 2025-08-27 eCollection Date: 2025-09-22 DOI:10.1021/jacsau.5c00867
Xiao-Xiao Chen, Xia Mu, Zhi-Yuan Li, Kun Peng, Qing-Hua Shen, Yue-Bin Zhang, Cai-Ping Tan
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引用次数: 0

摘要

相分离与RNA的转录、加工、翻译和代谢密切相关,调控RNA相分离可能是一种有效的抗肿瘤策略。然而,基于小分子的RNA相分离诱导剂尚未见报道。在此基础上,我们设计了一种Ru-(II)复合物(Ru1),它可以与RNA形成多价相互作用,并在体外诱导双链RNA (dsRNA)和单链RNA (ssRNA)的相分离。有趣的是,配体上的取代基,包括带正电的三苯基膦和羟基,在其诱导RNA相分离的能力中起着决定性的作用,这一点也被分子动力学模拟所证实。此外,ru1介导的光激活前相分离建立了一种新的RNA中心免疫激活机制,其中随后对RNA的光损伤触发视黄酸诱导基因I (RIG-I)途径。最后,我们证明Ru1可以显著改善肿瘤免疫微环境。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ru(II) Complex-Mediated Phase Separation Amplifies Photocatalytic RNA Damage to Stimulate RIG‑I Immunotherapy.

Phase separation is closely related to the transcription, processing, translation, and metabolism of RNA, and regulating RNA phase separation may serve as an effective antitumor strategy. However, small molecule-based RNA phase separation inducers have not yet been reported. Herein, based on our previous work, we designed a Ru-(II) complex (Ru1) that can form multivalent interactions with RNA and induce the phase separation of both double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA) in vitro. Interestingly, the substituents on the ligands, including the positively charged triphenylphosphine and the hydroxyl groups, play decisive roles in its capability to induce RNA phase separation, which is also confirmed by molecular dynamics simulations. Moreover, Ru1-mediated phase separation preceding photoactivation establishes a novel RNA-centric immune activation mechanism, wherein subsequent photodamage to RNA triggers the retinoic-acid-inducible gene I (RIG-I) pathway. Finally, we demonstrate that Ru1 can significantly improve tumor immune microenvironments.

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CiteScore
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