mRNA Immunogenicity Modulation

Creative Biogene is a forward-looking research institute as well as a leading custom service provider in mRNA-based drug research and development (R&D). In addition to optimizing stability and translation of mRNA, we also offer customized service for the regulation of mRNA immunogenicity. Exogenous mRNA can be recognized by various cell surface, endosomal as well as cytosolic innate immune receptors. The immunostimulatory is the inherent property of in vitro-transcribed (IVT) mRNA, and can be beneficial or harmful depending on the specific therapeutic applications. In applications such as vaccination, this property of IVT mRNA has added benefits. By virtue of its immune-stimulatory effect and intrinsic adjuvant activity, help to activate potent immune responses. However, for protein-replacement therapies, the feature of IVT mRNA has become a major disadvantage.

Mechanism of immune response induced by IVT mRNA

The immune response mechanism induced by IVT mRNA remains to be elucidated, involving the process mRNA recognition by cellular sensors and activation mechanism of the sensors. To date, there is some progress that has been made in this area. Two kinds of RNA sensors have been identified in cells, including toll-like receptors (TLRs, endosomal-RNA sensing) and RIG-I-like receptor receptors (RLRs, belong to cytosolic-RNA sensing). TLRs reside in the endosomal compartment of professional immune surveillance cells (such as DCs and macrophage), and are divided into the Toll-like receptors TLR3, TLR7 and TLR8. In immune cells, endocytosed IVT mRNA is recognized by TLRs and leads to interferon production. The cytoplasmic RIG-I-like receptor family acts as a pattern recognition receptor (PRR), including retinoic acid-inducible gene I protein (RIG-I), laboratory of genetics and physiology 2 (LGP2) and melanoma differentiation-associated protein 5(MDA5). These family members have a highly homologous structure. However, they differ in their RNA recognition as well as signaling capability.

Inflammatory responses to synthetic mRNA.Fig1. Inflammatory responses to synthetic mRNA. (Sahin, U., et al. 2014)

Services of mRNA immunogenicity regulation in Creative Biogene

As a leading service provider for mRNA-based drug research and development, we can support our customers with optimal mRNA immunoregulation strategy according to the desired applications. The services can be offered as a stand-alone service or integrated to provide the best combination.

Reduction of mRNA immunogenicity activity

To generate de-immunized IVT mRNA, we offer two major strategies. Among them, incorporation of modified nucleosides into the transcript is the common method and widely used. We offer a broad range of proved naturally occurring modified nucleosides for modification of mRNA immunogenicity activity, including but not limited to 2-thiouridine (s2U), 5-methyluridine (m5C), and pseudouridine (Ψ). These modified nucleosides have functions to suppress intrinsic adjuvant activity of IVT mRNA as well as promote mRNA translation. In addition, appropriate purification of IVT mRNA is critical for avoiding unwanted innate immune activation. We provide many techniques that have been developed for IVT mRNA purification, including high performance liquid chromatography (HPLC), fast protein liquid chromatography (FPLC) and magnetic beads technology.

Increasing the immunogenicity properties of mRNA

Since several molecules, such as protamine and granulocyte–macrophage colony-stimulating factor (GM-CSF), combined with naked IVT mRNA have been demonstrated feasible to promote the activation of antigen-specific immune responses. Our experts are glad to apply special expertise to help customers conduct modular testing with adjuvant molecules for selection of the optimal adjuvant-mRNA combinations. We offer traditional adjuvant molecules as well as taking advantage of mRNA intrinsic immunogenicity. Finally, it's important to point out that the modification of mRNA immunogenicity activity is affected by multiple factors, ranging from sequence optimization, the stringency of purification, and the level of innate immune sensing in the targeted cell types.

mRNA Immunogenicity Modulation

For more detailed information, please feel free to contact us or directly send us an inquiry.


  1. Zhang, C., et al. (2019). "Advances in mRNA vaccines for infectious diseases." Frontiers in Immunology, 10, 594.
  2. Gómez-Aguado, I., et al. (2020). "Nanomedicines to deliver mRNA: state of the art and future perspectives." Nanomaterials, 10(2), 364.
  3. Sahin, U., et al. (2014). "mRNA-based therapeutics—developing a new class of drugs." Nature reviews Drug discovery, 13(10), 759-780.
  4. Brumbaugh, J., Di Stefano, B., & Hochedlinger, K. (2019). Reprogramming: identifying the mechanisms that safeguard cell identity. Development, 146(23).
For research use only. Not intended for any clinical use.
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