- Off-target effects leading to toxicity - Ensuring efficient delivery to target tissues - Avoiding immune stimulation - Stability and uptake of RNAs/oligos in circulation - High cost of synthesis and formulation - Ethical concerns related to gene editing - Extensive regulatory testing is required for approval. Advances in chemistry, delivery materials, and computational modeling continue to help address these hurdles and facilitate the translation of gene-silencing technologies to the clinic. Careful dosing and strict oversight also help ensure their safe and ethical use.