Song's compatible team developed a manganese-based LNP-mRNA vaccine to enhance mRNA expression and improve immunogenicity, better preventing new crown mutant strains

Several vaccines have been approved to prevent COVID-19, including two mRNA vaccines, Comirnty (BNT162b2) developed by Pfizer/BioNTech, and Spikevax (mRNA-1273)
developed by Moderna.
With its unique advantages of high immunogenicity, fast production speed and low cost, mRNA vaccines have played an extremely effective role
in the fight against the COVID-19 pandemic.

However, immune evasion by emerging SARS-CoV-2 mutants, such as the current dominant epidemic strain Omicron, poses a significant challenge
to existing mRNA vaccines.
Therefore, it is imperative to develop more effective mRNA vaccines against new coronavirus mutant
strains.

Efficient antigen presentation by antigen-presenting cells (APCs), such as dendritic cells (DCs), is a prerequisite for the efficient functioning of mRNA vaccines, which requires adequate protein translation and APCs maturation
.
In addition, highly expressed co-stimulatory molecules on mature DCs provide secondary signals for the activation of immature T cells, and adjuvants can promote DC maturation and upregulate the expression
of DC co-stimulatory molecules.
Therefore, co-delivery of adjuvants is an effective strategy
to enhance the immune effect of mRNA vaccines.

Recently, the Song Xiangrong team of the State Key Laboratory of Biotherapy at West China Hospital of Sichuan University published a report in Science Advances entitled Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses Research paper
against SARS-CoV-2 variants.

Based on a novel ionizable lipid (IC8), the agonist manganese (2-valent Mn ion) of interferon gene stimulator (STING) was introduced to construct a novel mRNA delivery system with high immunogenicity, IC8/Mn-LNP
.
For the first time, it was demonstrated that Mn not only promotes the maturation of antigen-presenting cells (APCs) by activating the STING pathway, but also increases mRNA expression
by promoting lysosomal escape.

The study also used IC8/Mn-LNP to deliver the mRNA sequence of the full-length spike protein of the new crown mutant strain Delta or Omicron, both mRNA vaccines have a large number of specific IgG responses against Delta or Omicron, and also show strong neutralization ability against the new crown pseudovirus virus, Th1 cell biased immune response, and good
safety.

This study shows that IC8/Mn-LNP, a novel mRNA delivery system, has great potential in the development of Mn synergistically-enhanced mRNA vaccines, with strong immunogenicity and good safety
.

Co-delivery of adjuvants is an effective strategy
to enhance the immune effect of mRNA vaccines.
Agonists of toll-like receptors (TLRs) and interferon gene stimulating factor (STING) have been used as adjuvants in mRNA vaccines
.
However, TLR agonists can cause severe cytokine storms, which limits their clinical use
.
STING agonists, when used as adjuvants, induce relatively low levels of local and systemic inflammation
.

In September 2019, Miao et al.
published a paper in the journal Nature Biotechnology to develop an ionizable lipid library as an mRNA delivery vehicle to promote mRNA delivery in vivo and enhance anti-tumor effects
by activating the STING pathway.

Manganese (Mn), an essential element in many physiological processes, can stimulate the STING pathway by directly activating cGAS, but it is unclear
whether Mn can enhance the immune effects of mRNA vaccines.

Delivery systems protect mRNA from rapid degradation and help it be taken up and released by cells, which is essential
for efficient expression of mRNA in vivo.
Lipid nanoparticles (LNPs) have shown good efficacy and safety
in the only approved mRNA vaccine.

In July 2022, Song's compatible team published a research paper in the journal Advanced Functional Materials and found that ionizable lipids in LNPs significantly affect mRNA expression, and ionizable lipids with multiple tertiary amino nitrogen atoms significantly enhance the immunogenicity of mRNA vaccines compared with ionizable lipids of a single nitrogen atom used in the LNP of Moderna's mRNA vaccine, triggering a robust and durable humoral immune response
。

In the latest study, published in Science Advances, Song's compatible team designed and constructed a novel lipid nanoparticle containing manganese (Mn) and a novel ionizable lipid (IC8), IC8/Mn-LNP
.

The research team used IC8/Mn-LNP for delivery of mRNA, and then evaluated its immunogenicity after loading mRNA (IC8/Mn@S) encoding the full-length spike protein (S protein) of the SARS-CoV-2 mutant strain, and its protection against SARS-CoV-2 mutant
strains.

Manganese (Mn) enhances mRNA expression by promoting lysosomal escape and stimulates antigen-presenting cells (APCs) maturation
by activating the STING pathway.
In addition, IC8/Mn@S induced potent and durable IgG antibodies
against the new crown mutant strains Delta and Omicron at optimal doses (Mn:mRNA=1:1).

This study shows that the new mRNA delivery system, IC8/Mn-LNP, has great potential in the development of Mn synergistically-enhanced mRNA vaccines, with strong immunogenicity and good safety, and has good clinical application prospects
.