• The Role of Long Non-Coding RNAs in Modern Therapeutics: Challenges and Prospects
  • Seyedeh Negar Marashi,1,* Razieh Heidari,2 Seyed Abbas Mirzaei,3
    1. Department of Medical Biotechnology , School of medicine , Mashhad University of Medical Sciences , Mashhad , Iran
    2. Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
    3. Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran


  • Introduction: With the advancement of gene therapies and their entry into clinical trials, non-coding RNAs have gained increasing attention as therapeutic agents or targets. Long non-coding RNAs (LncRNAs) are among the most important genetic regulators, playing vital roles in controlling gene expression, epigenetic regulation, chromatin structure, and cellular functions. Studies have shown that changes in LncRNA expression patterns are associated with the development and progression of many diseases, including cancer, cardiovascular diseases, diabetes, and neurological disorders. Therefore, LncRNAs have emerged as promising therapeutic targets or tools for designing advanced treatments. Their use in therapy not only enables precise targeting of disease pathways but also paves the way for the development of personalized medicine in the future.
  • Methods: We conducted a literature search using Google Scholar and PubMed with the keywords 'nanoparticles,' 'delivery,' and 'lncRNAs.' Our objective was to identify and analyze peer-reviewed articles that discuss the challenges and prospects of utilizing long non-coding RNAs in modern therapeutics.
  • Results: Challenges in RNA Stability and Delivery Due to their complex structures and large molecular weights, LncRNAs present challenges in both study and delivery, and the success of LncRNA-based therapies depends on overcoming several key obstacles [1]. One of the major barriers is RNA instability in bodily fluids and difficulty crossing cell membranes due to their negative charge and large size. Naked RNAs are highly susceptible to degradation by nucleases, especially 2′-hydroxyl-dependent RNases. To enhance RNA stability, two main strategies have been employed: Chemical modifications of RNA structures, such as changes in the ribose sugar (e.g., 2′-O-methyl, 2′-fluoro) and phosphate backbone (phosphorothioate), which increase resistance to nucleases and reduce immune activation.Use of advanced delivery technologies such as liposomes, lipid nanoparticles (LNPs), and exosomes that protect RNA from degradation and facilitate targeted delivery [1,2]. Delivery Technologies and Therapeutic Applications Lipid nanoparticles (LNPs) are among the most popular carriers in clinical trials, and the success of mRNA COVID-19 vaccines has highlighted their potential for delivering LncRNAs. PEGylated RGD-modified liposomes have successfully delivered siRNA to the placenta in mouse models of preeclampsia [3]. Targeted nanoparticles have also shown efficacy in treating triple-negative breast cancer (TNBC) by silencing the oncogenic LncRNA DANCR [4]. Exosomes, due to their high biocompatibility, represent promising LncRNA delivery vehicles, although challenges such as high production costs and complex manufacturing processes limit their widespread use. LncRNA-Based Drugs in Clinical Trials The drug Andes-1537, which selectively targets mitochondrial long non-coding RNA (mtlncRNA), is currently in Phase 1 clinical trials and has demonstrated promising therapeutic effects against various tumor types. Andes-1537 binds to mtlncRNA and activates RNase H and DICER enzymes to generate microRNAs that disrupt the cell cycle and induce apoptosis [5].
  • Conclusion: Despite progress, safety concerns and delivery limitations have confined CRISPR/Cas9 systems and viral vectors primarily to basic research. Additionally, limited understanding of LncRNA functions and potential off-target effects remains the biggest hurdle for LncRNA-targeted therapies. Therefore, further elucidation of LncRNA mechanisms is essential for early diagnosis and the development of more effective treatments, especially for chronic diseases like cancer.
  • Keywords: nanoparticles, delivery, lncRNAs