Inhalable dry powder mRNA vaccines based on extracellular vesicles

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.

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