Put a ring on it: redesigning the delivery vehicles behind mRNA vaccines

The modification of lipid nanoparticles with aromatic rings and disulfide bonds enhances mRNA vaccine delivery.

Researchers at the University of Pennsylvania (PA, USA) have modified lipid nanoparticles (LNPs) to make mRNA vaccine delivery more precise, reducing the off-target effects associated with LNPs. The improved delivery systems demonstrated strong immune potency and reduced side effects at lower doses, with potential applications in cancer vaccines and autoimmune-disease treatments.

The lymph nodes serve as the hubs of the immune system, where specialized immune cells bring antigens to teach other immune cells what to recognize and attack. mRNA vaccines utilize this system, delivering mRNA encoding a harmless pathogen fragment that can prime the immune system to recognize the pathogen in future.

LNPs are the transport vehicles that deliver mRNA to the lymph nodes; however, as successful as mRNA vaccines are, LNP formulations can result in off-target delivery, often to the liver. If researchers can redesign these nanoparticles to steer them more precisely towards the lymph nodes, then a lower dose would be needed to achieve immunity.

To do this, the team at Penn built upon previous research that demonstrated improved LNP performance following the addition of a square-shaped aromatic compound to the ionizable lipid. They investigated whether other aromatic structures could produce similar effects, building the first library of variable ionizable lipids that employed benzene rings and bioreducible disulfide bonds.

Coming to a consensus: the development of a new mRNA vaccine

A new type of mRNA vaccine is more scalable and adaptable to continuously evolving viruses such as SARS-CoV-2 and H5N1.

Testing the redesigned ‘aroLNPs’ in animal models, the researchers packaged them with luciferase mRNA, which produces a light-emitting protein when expressed that allowed the team to determine where the LNPs were delivering their cargo.

Compared to the LNP formulations used in the Moderna COVID-19 vaccine, the top-performing aroLNPs delivered substantially less mRNA to the liver while accumulating just as much in the lymph nodes. These modified nanoparticles also produced antibody responses similar to those produced by FDA-approved formulations, while causing only a minimal increase in systemic proinflammatory cytokines, potentially reducing mRNA vaccine-associated side effects.

In future, aroLNPs could be harnessed for next-generation therapies, which often require the ability to fine-tune the immune response.

“This is really about precision,” concluded Michael Mitchell, senior author of the study. “If we can control where mRNA goes in the body, we can begin to tailor immune responses more deliberately, whether that means turning them up, turning them down or directing them toward a specific target.”