Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

RNAi therapeutics offer several advantages over the traditional small molecules and protein-based drugs. They could virtually target any genes with high selectivity, including those "undruggable" targets. The design and synthesis of RNAi molecules are relatively simple because they do not need a cellular expression system, complex protein purification, or refolding schemes [28] . Compared to the antisense oligonucleotides, RNAi is more potent and specific [29] . Despite its huge therapeutic potential, delivery remains to be a major barrier to the clinical application of RNAi therapeutics [30, 31] . For the treatment of respiratory disorders, pulmonary route of administration can deliver RNAi molecules directly to the site of action, thereby lowering the dose required while minimizing systemic adverse effects. The RNAi molecules can also avoid the rapid clearance by serum nuclease in the bloodstream. Moreover, inhalation is a non-invasive route of administration that is easily accepted by patients compared to parenteral administration, leading to better patient compliance [14, 32] . However, pulmonary drug delivery is a challenge with several key biological barriers, which are highlighted in Figure 2 .