Advanced approaches to overcome biological barriers in respiratory and systemic routes of administration for enhanced nucleic acid delivery to the lung.

introductionNumerous delivery strategies, primarily novel nucleic acid delivery carriers, have been developed and explored to enable therapeutically relevant lung gene therapy. However, its clinical translation is yet to be achieved despite over 30 years of efforts, which is attributed to the inability to overcome a series of biological barriers that hamper efficient nucleic acid transfer to target cells in the lung. AREAS COVERED: This review is initiated with the fundamentals of nucleic acid therapy and a brief overview of previous and ongoing efforts on clinical translation of lung gene therapy. We then walk through the nature of biological barriers encountered by nucleic acid carriers administered via respiratory and/or systemic routes. Finally, we introduce advanced strategies developed to overcome those barriers to achieve therapeutically relevant nucleic acid delivery efficiency in the lung. EXPERT OPINION: We are now stepping close to the clinical translation of lung gene therapy, thanks to the discovery of novel delivery strategies that overcome biological barriers via comprehensive preclinical studies. However, preclinical findings should be cautiously interpreted and validated to ultimately realize meaningful therapeutic outcomes with newly developed delivery strategies in humans. In particular, individual strategies should be selected, tailored, and implemented in a manner directly relevant to specific therapeutic applications and goals.