This review presents an integrated analysis of the current-state-of-the-art in nucleic acid nanotherapies and highlights the importance of nanotechnology in the delivery of nucleic acid therapies. While there is no one dominant nanodesign, the diversity of nanodesigns and delivery of different siRNAs, miRNA and DNA to inhibit more than 20 targets in seven disease states in Phase II/III clinical trials reflects the potential of nucleic acid therapies to treat intractable diseases and non-druggable targets. We provide benchmarks to aid in comparing the design, proof-of-concept studies and clinical trials. From this, we demonstrate the importance of generating a strategic framework for integrating clinical 'wish lists' for a means to treat intractable diseases with engineering 'design checklists' for nucleic acid nanotherapies.