RNA-based therapeutics offer transformative potential for treating devastating diseases. However, current RNA delivery technologies face significant hurdles, including inefficient tissue targeting, insufficient selectivity, and severe side effects, leading to the termination of many clinical trials. This review critically assesses the landscape of RNA-derived medicines, examining world-renowned mRNA vaccines (Spikevax, BNT162b2/Comirnaty) and RNA-based therapeutics like Miravirsen (anti-miR-122). It details the composition and clinical trial results of numerous modified short RNA drugs (e.g., siRNAs, miRNA mimetics/inhibitors) targeting various conditions. Prospects for RNA-based medicines are analysed for diseases with substantial societal impact, such as cancer, autoimmune disorders, and infectious diseases, with a focus on evolving delivery methods, including lipid nanoparticles, viral vectors, and exosomes. RNA-mediated macrophage reprogramming emerges as a promising strategy, potentially enhancing both delivery and clinical efficacy. This review highlights that while approved RNA therapies primarily target rare diseases due to delivery limitations, novel approaches in RNA modification, targeted delivery systems, and enhanced understanding of molecular mechanisms are crucial for expanding their application to prevalent diseases and unlocking their full therapeutic potential.

RNA-based drugs hold significant potential, offering promising new treatments for a wide range of diseases, especially those with a genetic basis. By leveraging RNA interference (RNAi) and other RNA-mediated mechanisms, these therapies can precisely modulate gene expression and address the root causes of genetic defects. RNA-based drugs hold significant potential for treating a range of diseases. However, the transition of these therapies from laboratory research to clinical applications has encountered hurdles. This review explores the composition and outcomes of clinical trials for various modified short RNA drugs. We detail their mechanisms of action, delivery systems—with a focus on lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates—and clinical efficacy in treating conditions such as transthyretin (TTR) amyloidosis. Our analysis reveals that while several RNAi-based drugs have achieved clinical approval, a critical unmet need remains: advanced delivery systems capable of precisely targeting diverse tissues, particularly outside the liver. We also underscore the importance of rigorous target validation utilising sophisticated bioinformatics tools and in vitro/in vivo assays to minimise off-target effects and ensure robust therapeutic efficacy. This review proposes a novel framework for optimising RNA drug development, emphasising the crucial interplay between delivery strategies, target specificity, and understanding disease-specific target biology.

Background: RNA therapeutics represent a rapidly advancing field with significant potential for treating viral infections and cancer. This review examines the current landscape of RNA-based strategies, including siRNA, miRNA mimics, and antisense oligonucleotides. For viral infections, the focus is on hepatitis B (HBV) and C (HCV), HIV, and SARS-CoV-2. Approaches include targeting viral transcripts directly (e.g., siRNAs against HBV surface antigen) or host factors critical for viral replication (e.g., anti-miR-122 miravirsen for HCV). The successful development of mRNA vaccines for COVID-19 is highlighted as a major breakthrough, demonstrating the feasibility of rapid RNA vaccine deployment. The manuscript reviews several RNA therapeutics in oncology that have reached clinical trials. These include TargomiR (a miR-16 mimic for mesothelioma), cobomarsen (an anti-miR-155 for lymphomas), and MRX34 (a miR-34a mimic for various solid tumours). The review also covers emerging candidates like an miR-221 inhibitor and various strategies for breast cancer, such as targeting Bcl-2, KRAS, and specific miRNAs. A critical challenge across both fields is developing efficient and safe delivery systems, including lipid nanoparticles, GalNAc conjugates, and bacterial minicells. Despite promising preclinical results, clinical translation has been hampered by issues like insufficient delivery efficiency to human tumours, toxicity, and the complex, interconnected regulatory networks of miRNAs, which can lead to unpredictable off-target effects. Conclusions: While RNA therapeutics hold immense promise, overcoming delivery barriers and enhancing understanding of RNA regulatory networks are essential for future success.