Nanocarriers for inhaled delivery of RNA therapeutics

RNA therapeutics are promising for the treatment of lung diseases where small molecules and biologics have failed to have much success in the past. While siRNA and mRNA drugs are now FDA-approved for rare diseases in the liver and as vaccines for infectious diseases, they became clinically established only after suitable advances in drug delivery platforms, such as the case of lipid nanoparticles. Localized delivery of RNA therapeutics through nanocarriers optimized for inhaled administration has the potential to address respiratory diseases without toxicity concerns from off-target effects. Here, we review recent clinical and preclinical progress of nanocarriers for inhaled RNA delivery, analyze the properties of nanocarrier-mediated FDA-approved drugs for respiratory diseases, and highlight compelling efficacy endpoints anticipated from ongoing clinical programs. We also present an overview of physiological challenges and opportunities that impact delivery of inhaled RNA therapeutics to the lungs. Finally, we discuss relevant models for preclinical testing, and translational considerations that can be used to help develop future nanocarriers for inhaled administration of RNA therapeutics.