Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium

Abstract

Nucleic-acid-based drugs can be designed to encode for therapeutic proteins of interest and therefore have the potential to treat a broad range of diseases. In vitro transcribed (IVT) mRNA has several properties that give it promise as a therapeutic including lack of insertional mutagenesis, the ability to transfect nondividing cells, and controlled protein expression. [1] Local delivery of IVT-mRNA to the lung is promising for the treatment of respiratory disease, for example, intratracheal delivery of IVT-mRNA encoding for surfactant protein B was demonstrated to restore expression in a deficient mouse model. [2] While intra-tracheal delivery enables small doses to be administered locally and in a wellcontrolled manner, it is invasive and lung deposition is limited to the upper airways. In contrast, noninvasive inhalation of therapeutics is a clinically used route of drug delivery that can allow for deposition throughout the entire bronchiolar and alveolar epithelium. [3] Nebulized delivery has been adopted in human clinical trials for inhaled delivery of CFTR-DNA to cystic fibrosis patients. [4] Promising yet modest improvements in lung function were reported and challenges remain in optimizing nucleic acid delivery to the lung. [5] As yet, inhaled delivery of mRNA has not previously been reported and requires the development of vectors that are efficient for cytosolic mRNA delivery, can be concentrated to high delivery have found that a cationic polymer, branched polyethylenimine 25 kDa (bPEI), can facilitate effective gene delivery via nebulization; [10,11] however, concerns regarding toxicity and accumulation of this nondegradable polymer have precluded

Cancer‐Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery

“…Aerosol delivery provides direct access to lung tissue and can be used as a delivery route for lung cancer . An inhalable cationic liposome formulation for plasmid DNA is in clinical trials to treat cystic fibrosis, and a hyperbranched PBAE nanoparticle recently was used for mRNA delivery to lung epithelium ( Figure ) . Patel et al reported that hDD90‐118 polyplexes remained stable after aerosolizing with a vibrating mesh nebulizer, which produced micro‐sized droplets ideal for distribution throughout lung tissue .…”

“…An inhalable cationic liposome formulation for plasmid DNA is in clinical trials to treat cystic fibrosis, and a hyperbranched PBAE nanoparticle recently was used for mRNA delivery to lung epithelium ( Figure ) . Patel et al reported that hDD90‐118 polyplexes remained stable after aerosolizing with a vibrating mesh nebulizer, which produced micro‐sized droplets ideal for distribution throughout lung tissue . They were able to transfect 24.6% of lung epithelial cells after a single dose, with transfection seen in all five loves of the lung .…”

“…Patel et al reported that hDD90‐118 polyplexes remained stable after aerosolizing with a vibrating mesh nebulizer, which produced micro‐sized droplets ideal for distribution throughout lung tissue . They were able to transfect 24.6% of lung epithelial cells after a single dose, with transfection seen in all five loves of the lung . Delivery to other tissues, including the liver, spleen, and heart, was negligible, and there was no observed local or systemic toxicity .…”

“…They were able to transfect 24.6% of lung epithelial cells after a single dose, with transfection seen in all five loves of the lung . Delivery to other tissues, including the liver, spleen, and heart, was negligible, and there was no observed local or systemic toxicity . While this platform has not been employed in lung cancer models, cancer treatment is an obvious potential application of these new inhalable technologies.…”

“…Particles also have a narrow size distribution before and after nebulization E). Reproduced with permission . Copyright 2019, Wiley‐VCH Verlag GmbH & Co. KGaA.…”