Pulmonary gene delivery—Realities and possibilities

Delivery of genetic material to tissues in vivo is an important technique used in research settings and is the foundation upon which clinical gene therapy is built. The lung is a prime target for gene delivery due to a host of genetic, acquired, and infectious diseases that manifest themselves there, resulting in many pathologies. However, the in vivo delivery of genetic material to the lung remains a practical problem clinically and is considered the major obstacle needed to be overcome for gene therapy. Currently there are four main strategies for in vivo gene delivery to the lung: viral vectors, liposomes, nanoparticles, and electroporation. Viral delivery uses several different genetically modified viruses that enter the cell and express desired genes that have been inserted to the viral genome. Liposomes use combinations of charged and neutral lipids that can encapsulate genetic cargo and enter cells through endogenous mechanisms, thereby delivering their cargoes. Nanoparticles are defined by their size (typically less than 100 nm) and are made up of many different classes of building blocks, including biological and synthetic polymers, cell penetrant and other peptides, and dendrimers, that also enter cells through endogenous mechanisms. Electroporation uses mild to moderate electrical pulses to create pores in the cell membrane through which delivered genetic material can enter a cell. An emerging fifth category, exosomes and extracellular vesicles, may have advantages of both viral and non-viral approaches. These extracellular vesicles bud from cellular membranes containing receptors and ligands that may aid cell targeting and which can be loaded with genetic material for efficient transfer. Each of these vectors can be used for different gene delivery applications based on mechanisms of action, side-effects, and other factors, and their use in the lung and possible clinical considerations is the primary focus of this review.