To achieve sustained vaccine-protein expression in cells, both the mRNA and LNPs should remain fully intact for as long as possible 8, 9, 10. It is well documented that fluid-mechanical shear forces impact the integrity of very long nucleic acid molecules 6, 7. However, an important challenge for delivery of LNP-formulated mRNA by inhalation is due to the process used to produce small droplets that can be inhaled: nebulization can exert such shear stress on the LNPs that they rupture, thereby exposing the mRNA 5 to omnipresent RNases in the extracellular space. Notably, mucosal targeting is thought to lead to a more efficient immunity against viruses such as SARS-CoV-2 4. Furthermore, it could reduce the drug dose required to reach effective concentrations, as it is delivered directly to the large, well-perfused and highly immunological active surface area of the airways. It is expected to minimize systemic exposure and side effects, bypass renal or liver clearance, and avoid invasive injections. ![]() Of the various routes of administrating LNP-formulated RNA therapeutics 1, 2, inhalation promises important advantages 2, 3. The LNPs provide essential protection against extracellular RNases to avoid premature RNA degradation and enable efficient intracellular delivery. Historically, the development of RNA formulations has been closely connected to that of lipid nanoparticles (LNPs), which are used to encapsulate the RNAs. The COVID-19 pandemic has brought the field of RNA therapeutics to the foreground by the very large scale application of mRNA vaccines. By comparing nebulization techniques with different energy dissipation levels we find that LNPs and mRNAs can be kept largely intact if the energy dissipation remains below a threshold value, for LNP integrity 5–10 J/g and for mRNA integrity 10–20 J/g for both vaccines. We find that a lower energy level in generating LNP droplets using the new nebulization method helps safeguard the integrity of the LNP and vaccine. We compare the new method with well-known nebulization methods used for medical respiratory applications. Here we present a novel nebulization method able to preserve substantially the integrity of vaccines, as tested with two SARS-CoV-2 mRNA vaccines. However, the nebulization process can rupture the LNP vehicles and degrade the mRNA molecules inside. A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory viruses. ![]() Nebulization of mRNA therapeutics can be used to directly target the respiratory tract.
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