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-temp...

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Published in:Matter 2022-09, Vol.5 (9), p.2960-2974
Main Authors: Popowski, Kristen D., Moatti, Adele, Scull, Grant, Silkstone, Dylan, Lutz, Halle, López de Juan Abad, Blanca, George, Arianna, Belcher, Elizabeth, Zhu, Dashuai, Mei, Xuan, Cheng, Xiao, Cislo, Megan, Ghodsi, Asma, Cai, Yuheng, Huang, Ke, Li, Junlang, Brown, Ashley C., Greenbaum, Alon, Dinh, Phuong-Uyen C., Cheng, Ke
Format: Article
Language:English
Subjects:
COVID-19
dry powder inhalation
exosomes
extracellular vesicles
lung
mRNA vaccine
nonhuman primate
spike protein
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Summary: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. 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. [Display omitted] •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 Research in extracellular vesicles (EVs) is important to the field of translational medicine to develop therapeutics that are limited by poor cellular targeting and efficacy. The biological composition of EVs can be exploited as drug-delivery vehicles that may be engineered for cellular targeting or eliciting specific immune responses through their functions in membrane trafficking and cellular signaling. With the molecular composition of EVs varying depending on their parent-cell origin, the derivation of EVs can further refine nanomedicine by utilizing nanoparticles that are recognized by specific cellular microenvironments. EVs are found in almost all biological fluids, opening the application of EVs as tailored drug-delivery vesicles to a wide range of diseases. Lipid nanoparticles have limitations in inhaled drug delivery, including low pulmonary bioavailability and unoptimized formulation. Lung-derived extracellular vesicles (Lung-Exos) may be naturally equipped for drug delivery to the lung. We determined the biodistributio
ISSN:2590-2385
2590-2393
2590-2385
DOI:10.1016/j.matt.2022.06.012