- Optimization of 4 Key Components of Lipid Nanoparticles (LNPs), the Vaccine Carrier… Successful Design to Target Desired Immune Organs

- Significant Improvement in Vaccine Side Effects such as Fever… Two Consecutive Articles Published in World-Renowned Journal 'Advanced Science (IF=14.1)'

Figure Caption: Design principles and effects of next-generation mRNA vaccine delivery systems

  A research team led by Professor Nam Jae-hwan of the Department of Biomedical Science at the Catholic University of Korea (President Choi Jun-kyu) has developed a next-generation mRNA vaccine delivery system that dramatically improves liver toxicity and side effects, which have been pointed out as limitations of existing mRNA vaccines, and increases immune efficiency.

 mRNA vaccines, which garnered global attention during the COVID-19 pandemic, utilize a method of encapsulating genetic information in tiny lipid nanoparticles (LNPs) and injecting them into the body. These LNPs consist of four key components: ionized lipids, phospholipids/helper lipids, sterols/cholesterols, and PEG lipids; however, research and development to date have focused solely on ionized lipids. Consequently, existing vaccines had a structural limitation in that, after vaccination, the signal was mostly concentrated in the liver rather than in the spleen or lymph nodes, which are immune organs. This acted as a primary cause of reduced immune formation efficiency, elevated liver enzyme levels, inflammation, as well as side effects such as fever and muscle pain. 

The research team succeeded in inducing the precise delivery of vaccine materials to desired immune organs within the body by newly designing the core lipid components that make up LNP. This research achievement was recognized for its outstanding technological capabilities, with two consecutive papers published in ‘Advanced Science (IF=14.1)’, a world-renowned journal in the field of materials science. 

The first study achieved a reduction in side effects by minimizing the accumulation of lipid components in the body. The research team utilized a vitamin backbone familiar to the human body to optimize the hydrophobic tail structure of ionized lipids and introduced ‘disulfide bonds’ that degrade easily within cells. Experiments using a primate (macaque monkey) model demonstrated the safety of the new vaccine delivery system, which significantly lowered cytotoxicity and the induction of inflammatory cytokines compared to existing methods, while greatly alleviating fever and muscle pain occurring after vaccination. 

The second study is a ‘targeted delivery’ technology that redesigns the in vivo transport pathway of LNP from the liver to the spleen. The research team newly designed a bile acid-derived sterol (CA-20) through molecular dynamics (MD) simulations. The novel LNP incorporating this significantly reduced the proportion of LNP heading to the liver compared to existing cholesterol-based LNP, while selectively delivering mRNA to the spleen, where immune cells are densely concentrated, thereby inducing the formation of powerful antibodies and cell-mediated immune responses. 

 Professor Nam Jae-hwan of the Department of Biomedical Science at Catholic University explained, “Until now, mRNA vaccine development has been limited to modifying a single lipid component, but these two studies have proven that by treating four lipid components as design variables, the safety of the vaccine and the target organ can be finely controlled,” adding, “This design principle can be widely applied to the development of not only infectious disease vaccines but also anticancer vaccines and immunotherapies.”

 This research achievement is highly significant in that it simultaneously secured the safety and efficiency of next-generation mRNA therapeutics by combining safe lipid design and tissue-selective delivery technology. It is expected to serve as an important cornerstone for the future expansion of mRNA technology beyond simple infectious disease vaccines into next-generation cancer treatments or gene therapy platforms. 

This research was conducted with support from the Ministry of Food and Drug Safety’s projects, ‘Development of Toxicity Assessment Technology for mRNA Vaccines, etc.’ and ‘Establishment of Safety Assessment Platform for mRNA-based Neoantigen Cancer Vaccines and International Cooperation.’ The study brought to fruition through multidisciplinary convergence research, with Professor Ki-Yeon Lee of the Department of Chemistry at the Catholic University of Korea, Professors Byung-Chul Kang and Hye-Won Yoon of the Seoul National University College of Medicine, Professor Sang-Myung Lee of the Chungbuk National University College of Veterinary Medicine, and Professor Won-Pil Lim of Lehigh University in the United States participating as co-corresponding authors. 

Address of the first research paper: https://doi.org/10.1002/advs.76539

Address of the second research paper: https://doi.org/10.1002/advs.76671

(Figure 1) Design Principles and Effects of Next-Generation mRNA Vaccine Delivery Systems 

mRNA vaccines deliver genetic information by encapsulating it in microparticles composed of lipid nanoparticles (LNPs). The research team implemented two strategies regarding the four lipids that make up these particles: ① synthesizing new ionized lipids to ensure they decompose well within the body (left), and ② replacing cholesterol with bile acid-derived sterols (right). The two different approaches converged on the same result. Specifically, delivery to the liver was reduced, while delivery was concentrated in the spleen, where immune cells are densely concentrated, thereby improving both safety and vaccine efficacy.

(Figure 2) Composition of mRNA Vaccine Lipid Nanoparticles (LNPs) and Two Design Strategies

MRNA vaccines deliver genetic information encapsulated in microparticles composed of four types of lipids (top). The research team modified ① the tail structure of the ionized lipids surrounding the mRNA to facilitate their degradation within the body, and ② replaced the cholesterol supporting the particles with a new sterol derived from bile acids (middle). As a result, the distribution of the particles within the body changed; delivery to the liver was significantly reduced, and the delivery concentrated in the spleen, where immunity is generated (bottom).