由于p53缺陷、表观遗传沉默和基因组丢失的改变，微RNA miR-34a成为最具临床相关性的抑癌微RNA之一。毫无疑问，如果能够克服miR-34a稳定性差、非特异性传递和传递相关毒性等问题，许多患癌症的患者将受益于miR-34a的替代治疗。在这里，我们强调了一种完全修饰的miR-34a版本（FM-miR-34a），当与简单合成的配体结合时，可以克服这些障碍。与部分修饰的版本相比，FM-miR-34a的稳定性高出数个数量级，同时不会影响其活性，可以更强效地抑制更多miR-34a的靶点。FM-miR-34a能够有效抑制增殖和侵袭，并在体内传递后导致内源性靶基因持续下调120小时以上。通过将FM-miR-34a与叶酸（FM-FolamiR-34a）结合，可以在体内靶向治疗，抑制肿瘤生长，甚至在某些小鼠中实现完全治愈。这些结果有能力将miR-34a重新确立为一种抗癌药物，为临床测试提供了强有力的理由。©2023. 作者。

Altered by defects in p53, epigenetic silencing, and genomic loss, the microRNA miR-34a represents one of the most clinically relevant tumor-suppressive microRNAs. Without question, a striking number of patients with cancer would benefit from miR-34a replacement, if poor miR-34a stability, non-specific delivery, and delivery-associated toxicity could be overcome. Here, we highlight a fully modified version of miR-34a (FM-miR-34a) that overcomes these hurdles when conjugated to a synthetically simplistic ligand. FM-miR-34a is orders of magnitude more stable than a partially modified version, without compromising its activity, leading to stronger repression of a greater number of miR-34a targets. FM-miR-34a potently inhibited proliferation and invasion, and induced sustained downregulation of endogenous target genes for >120 h following in vivo delivery. In vivo targeting was achieved through conjugating FM-miR-34a to folate (FM-FolamiR-34a), which inhibited tumor growth leading to complete cures in some mice. These results have the ability to revitalize miR-34a as an anti-cancer agent, providing a strong rationale for clinical testing.© 2023. The Author(s).