Inhalable dry powder mRNA vaccines based on extracellular vesicles

During the last two years the interest in vaccines and mRNA technology has changed dramatically due to the arised emergency. Luckily science was ready to act fast thanks to a longlasting experience in virus identification, vaccine development and mRNA technology. I am personally still very much impressed about the improvements on the vaccine solutions over this short period. Always being interested to learn about potential better ways to apply therapies I was intrigued by the following publication I would like to share with you this week.

(Popowski et al., Inhalable dry powder mRNA vaccines based on extracellular vesicles, Matter (2022), ttps://doi.org/10.1016/j.matt.2022.06.012

Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart.

Highlights

• Lung extracellular vesicles (Lung-Exos) can package mRNA and protein drugs
• Lung-Exos are deliverable through nebulization and dry powder inhalation
• Dry powder Lung-Exos are room-temperature stable up to 28 days
• Drug-loaded Lung-Exos can serve as an inhalable vaccine to illicit immune responses

Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes. Continue reading here the full publication

Discussion

Altogether, we have demonstrated the formulation and biodistribution of inhaled exosomes and Lipos in mouse and nonhuman primate (NHP) lungs. Exosomal and liposomal mRNA and protein cargo are stable and maintain biological function upon dry powder formulation and DPI, with a shelf life extending 28?days. We showed that lung-derived exosomes most efficiently evade mucoadhesion while maintaining higher exosomal mRNA and protein cargo deposition, retention, and distribution in lung than their Lipo counterpart. Lung-derived exosomes had the highest nanoparticle delivery to the bronchioles and parenchyma, suggesting that nanoparticle phenotypes that are native to the lung microenvironment have enhanced cellular targeting and bioavailability within the lung.

For the first time, we showed that dry powder formulation of lung-derived exosomes is room-temperature stable and is compatible with a clinically used DPI device for at-home administration. The?chlorocebus sabaeus?NHP model most closely replicates the human airway and respiratory physiology, and exosome delivery was verified in the upper and lower respiratory tracts through DPI administration. Lung-derived exosomes were retained in the primate lung 1?week after a single DPI dose, delivering functional mRNA and protein exosomal cargo to the nose and to the deep lung. Lung-derived exosomes are functional as an inhaled therapeutic and drug-delivery vesicle for both upper and lower respiratory diseases.

Additionally, lung-derived exosomes have enhanced efficacy for pulmonary disease applications. S-protein-encoding mRNA remains effective in exosomes after 1?month of room temperature storage when lyophilized. As an inhaled vaccine, S-protein-loaded lung-derived exosomes elicited stronger immune responses than their synthetic counterpart, emphasizing the immunological advantages of biological nanoparticles for inhaled vaccines. Mice vaccinated with S-protein-loaded exosomes were able to more rapidly clear pseudoviral infection than Lipos, further emphasizing the enhanced efficacy of exosomes. Lung-derived exosomes offer a unique room-temperature-stable nanoparticle drug-delivery system, with enhanced bioavailability, that can serve as an mRNA and protein drug-delivery vesicle tailored for lung diseases.