RT Journal Article SR Electronic T1 Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.06.23.497408 DO 10.1101/2022.06.23.497408 A1 John G. Yuen A1 Andrew Fesler A1 Ga-Ram Hwang A1 Lan-Bo Chen A1 Jingfang Ju YR 2022 UL http://biorxiv.org/content/early/2022/06/26/2022.06.23.497408.abstract AB MicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Its inherently pleiotropic nature make miRNAs strong candidates for the development of cancer therapeutics, yet despite its potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNA interference (RNAi) function. To demonstrate the general applicability of this approach to other tumor suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nM range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.Competing Interest StatementThe authors have declared no competing interest.