Targeting RNA Therapeutics to the Lung: Ten Years On.

Treating airways disease with biotherapeutics and RNA should be simple in principle: topical dosing by inhalation should offer direct access to lung epithelia, cells suited to treatment as they are often implicated in the pathology of heritable and infectious disease. The early hopes for using RNA and oligonucleotide therapeutics in such a fashion came to an abrupt stop in 2011 when we showed that inhalation of these drugs leads to their rapid systemic access and liver loading, where they exert substantial activity compared to the intended target tissue. Since then, success in vivo has been limited and often questionable given the natural propensity of lung epithelia to translocate these drugs to the bloodstream. Today, the advent of lipid nanoparticle RNA formulations in the guise of COVID-19 vaccines promises a quick solution to this problem. This talk will review progress to date with lung-targeted adenoassociated virus gene therapy, chemical conjugation, polymer encapsulation, and even extracellular vesicles in accessing lung cell cytosols for therapeutic delivery of RNA drugs.