MicroRNA in cancer therapy: breakthroughs and challenges in early clinical applications

Abstract

MicroRNAs (miRNAs) have emerged as pivotal regulators in cancer biology, influencing tumorigenesis, progression, and resistance to therapy. Their ability to modulate multiple oncogenic and tumor-suppressive pathways positions them as promising therapeutic tools or targets. This review examines the dual role of miRNAs in solid and hematological malignancies, starting from their dysregulation in various cancer types. Therapeutic approaches, including miRNA replacement and inhibition strategies, are discussed alongside innovative delivery systems such as lipid nanoparticles and exosomes. Despite their transformative potential, challenges persist, including off-target effects, immune activation, and delivery inefficiencies. Recent clinical trials demonstrate both progress and hurdles, underscoring the need for advanced strategies to optimize specificity and minimize toxicity. This review provides an updated comprehensive overview of the current landscape of miRNA-based therapies under early clinical investigation and explores future directions for integrating these approaches into precision oncology.

Keywords: Clinical trials; Early clinical trials; First-in-human; LNA; Locked nucleic acid; Non-coding RNA; Phase 1; miRNA; miRNA inhibitor; miRNA therapeutics; microRNA; ncRNA.

Fig. 1

miRNA Biogenesis and Its Potential as a Therapeutic Target in Cancer. miRNAs biogenesis is a multi-step process that begins in the nucleus where are transcribed as pri-miRNAs by RNA polymerase II. Then the pri-miRNAs are cleaved by the Drosha-DGCR8 complex into precursor pre-miRNAs that leave the cytoplasm by Exportin-5 where the enzyme Dicer further processes pre-miRNAs into mature miRNAs. The mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), where they guide degradation or repression of target mRNAs, ultimately affecting protein production. miRNAs regulate genes involved in cell growth, apoptosis, and differentiation, their dysregulation is often linked to cancer. They can act as either: OncomiRs (Oncogenic miRNAs)– Promote cancer by suppressing tumor suppressor genes, or Tumor Suppressor miRNAs– Prevent cancer by inhibiting oncogenes. This makes miRNAs promising therapeutic targets in cancer by miRNA inhibition– blocking oncomiRs with ASOs or miRNA mimics– restoring tumor suppressor miRNAs to suppress cancer growth

Fig. 2

Strengths and Challenges in miRNA-Based Therapeutic Approaches. miRNA-based therapies show significant promise for cancer treatment, but various challenges must be addressed. Chemical modifications of ASOs or advanced delivery systems help overcome key issues, including: delivery efficiency, stability and degradation, off-target effects, immune response, scalability and manufacturing, regulatory and clinical validation