Just as an architect’s blueprint guides builders, mRNA sequences guide our cells, instructing them on how to build proteins with exact specifications. These proteins can be identical copies of those found on infectious viruses or bacteria, and act as ‘training dummies’ for our immune system, teaching it how to effectively target the real invaders.
“mRNA vaccines have enormous potential because they provide a highly versatile platform that can be rapidly adapted to protect against emerging infectious diseases and treat cancers,” said Yi Yan Yang, a Distinguished Scientist at the A*STAR Bioprocessing Technology Institute (A*STAR BTI).
However, mRNA vaccine design can be tricky: being fragile, mRNA strands are often packaged in protective lipid nanoparticles (LNPs) that help them stay intact as they travel through the human body. But conventional LNPs can be a double-edged sword. They often contain polyethylene glycol (PEG)-lipids, which can trigger unwanted immune reactions and reduce vaccine efficacy.
As a potentially safer alternative to PEG-based LNPs, Yang and A*STAR BTI colleagues Gui Zhao, Chuan Yang, Yue Zhang and Brandon Yi Loong Seow recently developed a new class of biodegradable polycarbonate lipids with mannose and oligo (ethylene glycol) (OEG) groups, collectively called PCM lipids.
While many PEG-lipid substitutes focus on replacing PEG while preserving nanoparticle stability, Yang explained that PCM lipids were designed to do more: the OEG and mannose groups help provide a hydrophilic surface, while the mannose groups also act like ‘address labels’, directing PCM-engineered LNPs (PCM LNPs) to immune cells that kickstart immunity against pathogens.
In a recent comparison study of how various LNPs distributed themselves across different organs when injected into mice, the team found that commercial LNPs formulated from the PEG-lipid ALC-0159 (ALC LNPs) delivered mRNA to the liver, apart from the injection site and lymph nodes. In contrast, PCM LNPs showed much lower delivery to the liver; instead, they concentrated mRNA delivery at the injection site and lymph nodes, where immune responses are initiated. PCM LNPs were also much more effective at delivering mRNA into monocytes, macrophages and dendritic cells in the lymph nodes—key immune cells that help trigger and coordinate vaccine responses.
The researchers also did a head-to-head comparison of PCM LNPs and ALC LNPs when used to creating mRNA vaccines for H5N1, the virus behind avian influenza (a.k.a bird flu). They found that PCM LNPs outperformed ALC LNPs in stimulating robust immune responses in H5N1 mouse models, producing significantly higher antibody titres and proportions of immune cells able to kill infected cells.
“Furthermore, in repeated dosing studies, PCM-LNPs did not induce anti-PEG antibodies and generated only minimal and transient PCM-specific antibody responses,” explained Yang. “These results suggest that PCM-LNPs may be suitable for booster vaccinations or therapies requiring multiple administrations.”
The team is currently further optimising their PCM lipids to enhance their immune cell targeting efficiency and long-term storage stability. Beyond infectious diseases, the team also plans to apply PCM-LNPs to cancer vaccines.
“Our goal is to develop next-generation, PEG-free LNP technologies that can safely deliver mRNA repeatedly and selectively to specific cell types, thereby expanding the applications of mRNA therapeutics,” said Yang.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Bioprocessing Technology Institute (A*STAR BTI).
