No letter is useful until it safely reaches its intended recipient. This idea is critical in mRNA vaccines, where disease-fighting instructions for the immune system are ‘written’ in fragile strands of mRNA. When these messages reach the right cells, they can have a powerful impact, as demonstrated by the global success of COVID-19 mRNA vaccines. However, like letters lost in transit, mRNA vaccines can also be damaged en route or delivered to the wrong place.
To protect these delicate instructions, most mRNA vaccines today are ‘packaged’ in lipid nanoparticles (LNPs) coated with polyethylene glycol (PEG). Like plastic wrap shielding a paper package from damp, PEG helps LNPs stay stable in the bloodstream—but it can also cause complications.
“While effective, PEG doesn’t break down easily and can sometimes trigger unwanted immune reactions,” said Yi Yan Yang, a Distinguished Principal Scientist at the A*STAR Bioprocessing Technology Institute (A*STAR BTI). “With repeated doses, the body may begin to recognise PEG as foreign, reducing vaccine effectiveness. PEGylated LNPs can also lack precise targeting.”
Seeking a better solution, Yang recently led a team of A*STAR BTI and A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) researchers in a rethink of LNP design. “We wanted to build a smarter vaccine delivery vehicle: one that the body recognises, immune cells welcome, and mRNA can rely on to deliver its message where it matters most,” said Yang.
The team tested two innovative tweaks to LNPs. First, they replaced PEG coatings with biodegradable polypeptides, made from the same building blocks as natural proteins. “Polypeptides are more body-friendly, and can be broken down and cleared once LNPs deliver their cargo,” said Yang. “This reduces the risk of unwanted immune reactions from repeated dosing, which is crucial for vaccines that require boosters.”
Second, they added biological address labels onto LNPs: molecules of mannose sugars, which guide the LNPs toward antigen-presenting cells (APCs). Acting as the immune system’s teachers, APCs are central to vaccines; they process vaccine antigens and present them to other immune cells, triggering strong and long-lasting immune responses.
When tested in mice, the team’s systems behaved very differently from standard PEGylated LNPs, selectively travelling to the lymph nodes with very little accumulation in the liver. “Seeing our nanoparticles naturally home in on lymph nodes was both surprising and exciting,” said Jinyue Zeng, a Senior Scientist at A*STAR BTI. “They’re the immune system’s command centres, where APCs gather to initiate immune responses.”
The team noted that this precise targeting could not only enhance mRNA vaccines for infectious diseases, but also cancer vaccines, where accurately directing immune responses is critical.
Looking ahead, the team has proactively designed their technology with manufacturing in mind. “The polypeptide lipids in our system are inherently scalable, and their synthesis follows a well-established process that can be adapted to large-scale production,” Yang added.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Bioprocessing Technology Institute (A*STAR BTI) and the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).
