Inhalable COVID-19 Vaccines: Recent Findings and Breakthroughs

Blog post by Nina Culum, MSc

Great strides have been made in combating SARS-CoV-2, and regulatory approval of COVID-19 vaccines continues worldwide. In fact, as of September 2021, 19 vaccines have been approved in at least one country [1]. However, most approved vaccines require intramuscular injection, produce antibodies in the blood, and do not necessarily elicit mucosal immune responses [2]. Given that SARS-CoV-2 is primarily transmitted through respiratory droplets, with respiratory mucosa being the main viral entry route, is intramuscular administration the most effective vaccine delivery method to fight COVID-19? In this blog post, we have summarized a study published this month in Nature Biomedical Engineering that presents an alternative approach to vaccine administration. In it, the authors describe the design and preclinical testing of an inhalable COVID-19 vaccine based on lung-derived exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain (RBD) [2].

What exactly are exosomes?

Exosomes, a subclass of extracellular vesicles, are complex, nanoscale, membrane-bound vesicles that are secreted by nearly all cells into human biofluids [3]. Importantly, exosomes are a mediator of intercellular communication as they transfer membrane and cytosolic proteins, lipids, and RNA between cells over long distances, which can be exploited for vaccine development [3, 4]. While many exosome-based vaccine approaches have been applied to cancer treatment, immunization strategies have also shown promise against infectious viral diseases including human immunodeficiency virus, hepatitis B, and influenza, and are therefore being investigated for use against COVID-19 [3].

Exosome secretion from cells

3D illustration of cells secreting exosomes.

How does the inhalable exosome-based vaccine work?

By conjugating RBD onto the surface of lung spheroid cell-derived exosomes (RBD-Exo), Wang et al. have engineered a virus-like particle that emulates native virus morphology. When inhaled, RBD-Exo produces neutralizing antibodies against SARS-CoV-2 and triggers immune responses in the lung to suppress viral uptake by the lung epithelium [2]. In mice, two RBD-Exo doses induced antibody production and facilitated rapid clearance of SARS-CoV-2 mimics; furthermore, nebulization administration (i.e., inhalation) induced faster viral clearance compared to intravenous injection. The authors also assessed the protective effects of the vaccine in hamsters infected with high doses of SARS-CoV-2, and demonstrated that severe pneumonia could be attenuated and inflammatory infiltrates could be reduced.

What are the practical implications of an exosome-based COVID-19 vaccine?

Unfortunately, clinical translation of exosome-based approaches suffers heavily from reproducibility issues, as well as challenges in scaling up production and purification [5]. However, establishing mucosal immune protection is critical in respiratory diseases like COVID-19, which is a limitation of common intramuscular vaccines [2]. Although inhalable vaccines are not a one-size-fits-all approach (i.e., may not be recommended for individuals who have baseline respiratory complications), room temperature vaccine stability will greatly benefit populations who do not have access to deep freezers, as is required for currently approved COVID-19 vaccines. Despite these promising early findings, further studies are required to assess the feasibility of employing these exosome-based vaccines in clinical settings.

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About the Author

About the Author

Nina Culum, MSc

Nina Culum graduated from the University of Western Ontario with a Master of Science in physical and analytical chemistry. During her graduate studies, she fabricated plasmonic nanohole arrays to capture extracellular vesicles and detect cancer by surface-enhanced Raman spectroscopy. Prior to attending UWO, Nina completed her Bachelor of Science in chemistry at the University of Waterloo.


  1. Sharma K, Koirala A, Nicolopoulos K, Chiu C, Wood N, et al. Vaccines for COVID-19: where do we stand in 2021? Paediatr Respir Rev. 2021;39:22-31. DOI: 10.1016/j.prrv.2021.07.001.
  2. Wang Z, Popowski KD, Zhu D, López de Juan Abad B, Wang X, et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. Nat Biomed Eng. 2022. DOI: 10.1038/s41551-022-00902-5. Online ahead of print.
  3. Santos P, Almeida F. Exosome-based vaccines: history, current state, and clinical trials. Front Immunol. 2021;12:711565. DOI: 10.3389/fimmu.2021.711565.
  4. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373-83. DOI: 10.1083/jcb.201211138.
  5. Huda MN, Nurunnabi M. Potential application of exosomes in vaccine development and delivery. Pharm Res. 2022. DOI: 10.1007/s11095-021-03143-4. Online ahead of print.