• Therapeutic targeting of Long Non-Coding RNAs in cancer: Emerging Strategies and Nanodelivery Approaches
  • Nooshafarin Shirani,1,* Neda Abdi,2
    1. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
    2. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.


  • Introduction: RNA therapeutics (RNATx) are being developed to fight cancer by directly targeting or modifying RNA molecules, including long non-coding RNAs (lncRNAs). lncRNAs play a crucial role in the regulation of cancer growth, metastasis and drug resistance. They can be easily detected in the saliva, serum, plasma, urine and tissue of cancer patients. Due to their flexible and complex structures, lncRNAs can be targeted while they are integrated into cellular complexes. Consequently, various strategies have been developed to suppress oncogenic lncRNAs, restore tumor-suppressive lncRNAs, and interfere with their functions. This review provides an in-depth analysis of various strategies currently used to regulate the expression and function of long non-coding RNAs (lncRNAs) for therapeutic purposes. Key strategies discussed include antisense oligonucleotides (ASOs), RNA interference (RNAi) techniques, CRISPR-based engineering of lncRNAs, and the use of small molecules, aptamers and nanobodies. In addition, methods such as nanocarriers like polymers, liposomes, exosomes, adeno-associated viruses (AAV) and microbubbles will be presented to facilitate the targeted delivery of therapeutics into tumor cells.
  • Methods: A comprehensive literature search was conducted to review recent studies on therapeutic approaches targeting lncRNAs in cancer treatment. We examined databases such as PubMed, Scopus, Google Scholar and Web of Science using keywords such as "lncRNA", "cancer therapy", "ASOs", "siRNAs", "CRISPR-based engineering", "targeted therapy", "nanocarriers" and "targeted drug delivery systems". The selected studies were thoroughly analyzed to gather information on innovative methods for the targeted use of lncRNAs as a therapeutic approach to fight cancer. Furthermore, the research focused on different systemic delivery methods for therapeutic agents. Both in vitro and in vivo studies were included to provide a comprehensive overview of the existing research landscape.
  • Results: The analysis identified potential therapeutic strategies targeting cancer-associated lncRNAs to modulate their expression or function. Antisense oligonucleotides (ASOs) are synthetic, single-stranded nucleotides that are typically 13 to 22 nucleotides in length. They are designed to bind to complementary RNA sequences by Watson-Crick base pairing and thus modulate gene expression. For example, research has shown that delivery of the ASO LLNLR-299G3.1 lncRNA specifically through the plCSA-BP nanoparticle to ESCC tumor tissue can effectively treat LLNLR-299G3.1 lncRNA- an oncogenic lncRNA associated with ESCC- by suppressing tumor progression and significantly improving animal survival in vivo. Another potential approach is the use of small interfering RNAs (siRNAs), double-stranded RNA molecules typically 20 to 25 nucleotides in length. siRNAs can selectively silence cancer-related genes through sequence-specific binding. A recent study demonstrated that silencing the collaborative lncRNA CCAT1, in combination with the delivery of curcumin using colloidal silica nanoparticles (CSNP) to HT-29 cells, may provide a promising strategy for anti-cancer treatment in colorectal cancer. Moreover, CRISPR/Cas9 technology can be employed to switch off mutated or overexpressed oncogenes. For example, a study by Zhu et al. identified 51 lncRNAs as either positive or negative regulators of liver cancer proliferation using the generation of the first paired gRNA lentiviral CRISPR library.
  • Conclusion: The ability of lncRNAs to modulate various cellular signaling pathways, influence gene expression and display tumor-specific expression patterns underlines their potential as promising therapeutic targets. Consequently, the development of nanotherapeutic strategies centered on lncRNAs could significantly broaden the spectrum of druggable targets and serve either as a valuable adjunct to conventional approaches or as a primary modality for cancer treatment. However, several critical challenges and limitations remain, including concerns regarding tolerability, toxicity, off-target effects, in vivo validation of therapeutics and functional evaluation, which require further investigation.
  • Keywords: Cancer, RNATx, lncRNAs, nanodelivery, targeted drug delivery.