MicroRNA (miRNA) 分子在多种疾病中发挥着至关重要的作用，这使得 miRNA 成为药物化学中一个新兴领域。核糖核酸酶靶向嵌合体 (RIBOTAC) 为 RNA 降解提供了一种引人注目的方法。然而，基于小分子的RIBOTAC需要昂贵且耗时的筛选过程，并且由于其长度短且缺乏二级结构而难以直接靶向miRNA。基于反义寡核苷酸（ASO）的RIBOTAC易于设计，但细胞渗透性较差。但两者都缺乏肿瘤靶向的特异性。本研究基于ASO设计了第一个Aptamer-RIBOTAC（ARIBOTAC）嵌合体，以肿瘤细胞特异性的方式实现miRNA的精确降解，从而实现癌症的精准治疗。这种嵌合体表现出非凡的能力，可以特异性识别和进入癌细胞，触发内源性 RNase L 的局部激活，并选择性地切割与 ASO 互补的 miRNA。通过降解致癌 miR-210-3p 和 miR-155-5p，ARIBOTAC 策略在体外和体内的有效性和普遍性得到了验证。这些发现强调了 ARIBOTAC 策略作为通过精确靶向癌症相关 miRNA 进行癌症治疗的一种有前景的途径的潜力。© 2024 Wiley‐VCH GmbH。

MicroRNA (miRNA) molecules play crucial roles in a variety of diseases, making miRNA targeting a burgeoning field in medicinal chemistry. Ribonuclease targeting chimeras (RIBOTACs) present a compelling approach for RNA degradation. However, small molecule-based RIBOTAC requires an expensive and time-consuming screening process, and is difficult to directly target miRNA due to its short length lacking secondary structure. Antisense oligonucleotide (ASO)-based RIBOTAC is easy to design but with poor cell permeability. While both of them lack the specificity for tumor targeting. In this study, the first Aptamer-RIBOTAC (ARIBOTAC) chimera is designed based on ASO to achieve precise degradation of miRNA in a tumor cell-specific manner for precise cancer therapy. This chimera exhibits a remarkable ability to specifically identify and enter cancer cells, trigger localized activation of endogenous RNase L, and selectively cleave miRNAs that are complementary to ASO. The efficacy and universality of the ARIBOTAC strategy both in vitro and in vivo by degrading oncogenic miR-210-3p and miR-155-5p are validated. These findings underscore the potential of the ARIBOTAC strategy as a promising avenue for cancer therapy by precisely targeting cancer-associated miRNAs.© 2024 Wiley‐VCH GmbH.