mRNA vaccine has become a major weapon against the COVID-19 pandemic. Owing to its excellent features, especially the participation of protein translation without entering into the nucleus thus avoiding gene integration, mRNA vaccines have become an emerging hot research area. On the other hand, there are a number of disadvantages associated with mRNA vaccines, such as their large molecular sizes and easily being degraded by enzymes; the success of an mRNA vaccine strongly depends on the quality of its carrier. A high-quality carrier can efficiently protect mRNA and enable it effectively and safely cross the cell membrane to reach the cytoplasm to show great potential against diseases. Most carriers for mRNA delivery are lipid-based as they can enhance the oral bioavailability of drugs by pre-dissolving drugs in lipid carriers, which can increase dissolution and solubility and improve drug permeability in the gastrointestinal tract.<br/> <br/>It is a great challenge to predict the structure of an mRNA vaccine due to the large size of nanoparticles. It is impractical to conduct all-atom molecular dynamics simulations (MDS) for the whole vaccine. In this work, we conducted a large-scale MDS for a set of small RNAs with high-quality crystal structures residing in micelles formed by 24 lipids which are common ingredients of mRNA vaccine carriers. For each RNA/lipid system, the structural stability of the whole nanoparticle and the RNA structure was characterized using multiple metrics including the radius of gyration, and the RMSD of the RNA. The binding affinity between RNA and its carrier was also calculated using the end-point MM-PBSA-WSAS method. The rules for selecting the proper lipid carrier for a given RNA sequence have been established. Those rules can be useful in conducting rational carrier design for the whole mRNA vaccine.

Rational design of lipid-based carriers for delivering small RNAs through MD simulations and free energy analysis

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