113-O12B the lipid send LNP to lymph node
Introduction
The paper “Lipid Nanoparticle-Mediated Lymph Node-Targeting Delivery of mRNA Cancer Vaccine Elicits Robust CD8+ T Cell Response” provides insightful information about the current status of mRNA-LNP (Lipid Nanoparticle) systems for immunization. mRNA-LNP systems have been highly successful, particularly highlighted by their use in COVID-19 vaccines. These systems offer rapid production, safety, and high immune response, with the advantage of transient expression of antigens, reducing mutation risks associated with DNA vaccines. Furthermore, mRNA cancer vaccines can encode various antigens and induce stronger humoral and cellular responses compared to traditional vaccines.
Why Target the Lymph Node (LN)?
Lymph nodes are central to initiating and amplifying immune responses. Targeting LNPs to lymph nodes ensures a more direct and effective stimulation of the immune system, particularly T cells, which are crucial for combating cancer. This targeted approach not only enhances immune response but also minimizes potential side effects, which is a significant advancement over current mRNA-LNP systems that often result in undesired antigen expression in non-lymphoid organs like the liver. Therefore, lymph node targeting can improve vaccine efficacy and safety, making it a promising strategy for future mRNA vaccine development.
Results Showing 113-O12B Targeting the LN:
The efficacy of the 113-O12B lipid nanoparticle (LNP) in targeting lymph nodes (LN) for mRNA vaccine delivery was demonstrated through several experiments. A key experiment compared 113-O12B with ALC-0315. The results showed that 113-O12B had significantly reduced mRNA expression in the liver and higher expression in LNs after subcutaneous injection, indicating a superior LN-targeting ability (Top figure D). This targeted delivery was shown to enhance the CD8+ T cell response significantly, as evidenced by the therapeutic effect against an OVA-transduced B16F10 tumor model (OVA mRNA plasmid). Moreover, the 113-O12B encapsulated with a different antigen (TRP2) also exhibited excellent tumor inhibition. This indicates the broad applicability of 113-O12B for various antigens in cancer treatment and its potential as a platform for next-generation mRNA vaccines.
Formulation of 113-O12B LNP:
The lipid composition of the 113-O12B lipid nanoparticle is carefully designed to optimize its targeting ability to lymph nodes. The components include cholesterol (Chol), dioleoylphosphatidylcholine (DOPC), and 12-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG), formulated at a specific weight ratio. These components are selected for their roles in enhancing the stability, delivery efficiency, and biocompatibility of the nanoparticles.
| Component | Role in Lipid Nanoparticle | Molar Ratio |
|---|---|---|
| 113-O12B | Active lipid component | 50 mol% |
| Cholesterol (Chol) | Provides stability and structure to the lipid bilayer | 38.5 mol% |
| Dioleoylphosphatidylcholine (DOPC) | Contributes to the formation and fluidity of the lipid bilayer | 10 mol% |
| DMG-PEG | Offers steric stabilization, reducing clearance and extending circulation time | 1.5 mol% |
Criticals:
Critical 1: The 113-O12B is relatively unstable. There two factors which are causing the problem: disulfide bond(S-S bond) and ester bond. The stabiliby is making some trouble for its synthesis, and also later on as product, we should be careful with its purfity. Therefore, this stability issue is a potentially herdal for its industrial usage.
Critical 2: 113-O12B still leakage to liver. As stated clearly on the paper the 113-O12B leaks to liver. Moreover, it is quite visiable the ALC0315 still send LNPs to the LN (Top Figure, luciferase expression). And from the tumor experiment, we did not see the 113-O12B is showing expotential superial result compare to ALC0315. Therefore, we need to see more systematice result to be convinced that 113-O12B LNP is better than ALC0315 LNP because of it LN targeting specificity.
Order option:
ALC0135, OVA mRNA expression plasmid