Recent advances in the application of polymeric nanoparticles to the pulmonary delivery of mRNA.

Messenger RNA (mRNA)-based therapeutics offer the potential to treat a variety of pulmonary disorders that arise due to genetics, infectious diseases, and chronic respiratory conditions. However, various physiological barriers in the lungs, such as mucociliary clearance, macrophage phagocytosis, and lung surfactant interference, present challenges for efficient mRNA delivery. Polymeric nanoparticles (NPs) have emerged as a therapeutic platform for delivering mRNA therapeutics due to their stability, tunability, and controlled release properties, making them suitable and potentially ideal for encapsulating and protecting mRNA molecules for delivery in vivo. Continued advances in polymer and NP design have improved mucus penetration and cellular uptake upon lung delivery; further, administration via local and systemic routes enable modulation of NP biodistribution. These advancements benefit the potential treatment of a range of pulmonary diseases, including viral infections, cystic fibrosis (CF), asthma, and lung cancer, by facilitating immune modulation and genetic therapy delivery. In this review, we explore how polymeric NPs address disease-specific requirements and physiological challenges to expand the potential for therapeutic mRNAs in the lung.