Folate-mediated Delivery of Tumor-Suppressive Mirna-34A to Treat Osteosarcoma

Osteosarcoma is a common type of bone cancer primarily observed in children, teenagers, and young adults. Current treatments (including surgery, chemotherapy, and radiotherapy) are invasive and induce aggressive side effects. Alternative approaches such as using microRNAs (miRNA) are emerging as promising anticancer agents. miRNA modulates tumorigenesis via tumor-suppressive and oncogenic miRNAs. Tumor-suppressive and oncogenic miRNAs respectively downregulate oncogenic and tumor-suppressive mRNA transcripts. Hence, leveraging the anticancer activity of tumor-suppressive miRNAs appears as a viable anticancer treatment approach. The overarching challenges with miRNA therapy are 1) achieving specific non-toxic delivery of tumor-suppressive miRNA to cancer cells, and 2) enhancing the stability of the miRNA, which can be degraded by nucleases. To circumvent these obstacles, we developed a folate-conjugated fully modified miRNA-34a that specifically targets osteosarcoma cells, which often overexpress folate receptor-α on their surface. The fully modified miRNA-34a bears phosphorothioate linkages at the 3’ and 5’ ends of the sense and antisense strands which significantly reduces nucleases attack. The substitution of the 2’ hydroxyl with 2’ methoxy and 2’ fluoro groups in an alternative fashion further enhances stability. Overall, the fully modified miRNA-34a shows continuous downregulation of target genes 120 hours post-delivery in breast cancer in-vivo models. Here, we present preliminary results for folate-mediated delivery of fully modified miRNA-34a in osteosarcoma samples. This study highlights the potential of miRNA-34a as a safe and effective anticancer agent for osteosarcoma treatment. Iman T. Mevaa, Ahmed M. Abdelaal, Ikjot S. Sohal, Shreyas G. Iyer, Kasireddy Sudarshan, Harish Kothandaraman, Nadia A. Landman, Philip S. Low, Andrea Kasinski. Folate-mediated delivery of tumor-suppressive miRNA-34a to treat osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1864.