Redesigning miR-34a: structural and chemical advances in the therapeutic development of an miRNA anti-cancer agent.

MicroRNAs (miRNAs) represent a promising class of therapeutics due to their ability to down-regulate multiple genes simultaneously. This offers a significant therapeutic advantage in cancer, where heterogeneity often activates different pathways in different patients. Chemical modifications to the miRNA help overcome challenges associated with nuclease susceptibility, high immunogenicity, and the need for high or repeated dosing to achieve therapeutic effects. The main chemical modifications include changes to the ribose and backbone. Ribose modifications, including 2'-O-methyl and 2'-fluoro, improve nuclease resistance and plasma stability and lower the immunogenicity of the miRNA. Phosphorothioate (PS) backbone modifications increase resistance to nucleases and prolong circulation by enhancing serum protein affinity. Integrating these stabilizing chemical modifications with ligand targeting allows for specific delivery of the chemically modified miRNAs to tumors and metastases, bypassing bulky delivery vehicles and improving penetration into dense tumor architectures. Enhancements to ligand chemistry can also overcome endosomal entrapment. Incorporating many of the modifications discussed in this mini-review, the first fully modified version of miR-34a (FM-miR-34a) was developed, marking a significant milestone as the first fully modified miRNA to demonstrate substantial in vivo activity. Ongoing optimization of the chemical modifications and ligand chemistry, and integrating artificial intelligence into the design process are expected to further extend the potential for delivering on the promise of using these Nobel Prize-winning miRNAs as anti-cancer agents.