Scientists from the Massachusetts Institute of Technology (MIT) and elsewhere have published a paper in Science Advances that describes a type of nanoparticle for delivering vaccines called a metal organic framework (MOF) that can potentially provoke a strong immune response at lower doses. The paper is titled “Zeolitic Imidazolate Frameworks Activate Endosomal Toll-like Receptors and Potentiate Immunogenicity of SARS-CoV-2 Spike Protein Trimer.” 

In the study, which was done in mice, the researchers showed that the MOF successfully encapsulated and delivered part of the SARS-CoV-2 spike protein while simultaneously acting as an adjuvant once it broke down inside cells. More work is needed to ensure that the particles can be used safely in human vaccines, but these early results are promising. 

“Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant,” according to Ana Jaklenec, PhD, a principal investigator at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors on the study. “We were able to achieve very specific responses to the COVID-19 protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate.”

The MOF used in this study, called zeolitic imidazolate frameworks 8 or ZIF-8, is a lattice of tetrahedral units made up of a zinc ion attached to four imidazole molecules. Particles typically have diameters that are between 100 and 200 nanometers, making them small enough to get into the lymph nodes directly or through immune cells like macrophages. Prior studies showed that ZIF-8 particles can significantly boost immune responses. What is unclear is exactly how they activate the immune system. 

To answer that question, the researchers devised an experimental vaccine consisting of SARS-CoV-2 receptor-binding protein embedded in ZIF-8 particles. Once the particles entered the cells, the MOFs broke down releasing their viral protein cargo. The imidazole components of the MOFs then activate the toll-like receptors, which help to stimulate the innate immune response. 

RNA sequencing of lymph node cells from the vaccinated mice showed various immune related pathways were activated in response to the vaccine including the TLR-7 pathway, which led to greater production of cytokines and other inflammatory molecules. They also observed that mice vaccinated with the particles had a much stronger response to the viral protein, than those that received just the protein alone. 

Before these particles could be used in vaccines, scientists would have to evaluate not only their safety but also whether they could be scaled up for manufacturing on a larger scale. However, even if ZIF-8 does not work out, the researchers believe that their findings could help guide efforts focused on similar nanoparticles for delivering subunit vaccines, which are usually easier and cheaper to manufacture than mRNA vaccines.

“Designing new vaccines that utilize nanoparticles with specific chemical moieties, which not only aid in antigen delivery but can also activate particular immune pathways, have the potential to enhance vaccine potency,” Jaklenec noted. “Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines.”

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