One of the major issues that hinders the ncRNA therapy is the stability of the single stranded RNA molecule. RNA is typically single stranded therefore slightly unstable as compared to dsDNA molecules. This however can be overcome by fabricating the single stranded RNA to double stranded RNA(dsRNA). This is quite effective as the dsRNA is more stable at room temperature and has a longer shelf life.
Second major issue is the cell/tissue/organ specific targeting of the RNA molecules. Generally, this is overcome by containing the dsRNA in a lipid nanoparticle and using that as a ligand to bind to a receptor on the surface of the target cell. The lipid particles are taken into the liver cells through their specific receptors and this mechanism seems to be effective at targeting the liver cells/cancer.
Another organ with a relatively easy delivery mechanism is the eye. This requires an invasive technique of directly injecting the ncRNA of interest directly into the eye. These techniques are not only invasive but also don’t ensure if all the cells in the target organ are being targeted by the ncRNA of interest.
Additional issues arise once the RNA molecule enters the cell. One of the issues being the immune system. Our immune system can recognize RNA using the intracellular pathogen associated molecular pattern (PAMP) receptors and extracellular toll-like receptors (TLR). Activation of the receptors leads to a cytokine (IFNy-Interferon gamma) mediated immune response. Common applications to overcome the immune response include second generation chemical modifications. This process includes the introduction of small one at a time chemical modifications to avoid the immune response. However, there are some reports of adverse immune responses in clinical trials employing such modified reagents. There’s no fixed answer to  issues with immunogenicity and ncRNA therapy.
Modified adenovirus vectors have been used extensively in many clinical trials as a ncRNA delivery mechanism. In particular, adenovirus vector is considered an efficient delivery system due to its stability within live cells and non-pathogenicity. Even though viral transfections have achieved significant results in basic research, one of the issues is the non-specificity leading to off target transfections. Further research needs to be done to improve the accuracy of viral transfections for future tests and clinical trials.