Lung-related diseases, including viral infections, tumors, and hereditary diseases, pose a great threat to human life and health. However, the cure for these diseases is still limited. With the development of various key technologies, mRNA drugs can not only treat diseases directly at the transcriptional level, but also can be rapidly transformed into new drugs only by modifying the mRNA sequence, which provides a new strategy for the cure of lung diseases.

Lipid nanoparticles (LNPs) are one of the most successful nucleic acid drug delivery platforms so far, which can promote cell uptake of mRNA, and prevent its degradation during biological circulation. However, the low stability of LNP-mRNA pharmaceutical preparations hinders the development of related drugs, for example, several mRNA vaccines on the market can only be stored for 1 to 2.5 months at 4 °C, affecting the promotion and use of these products, and increasing the economic cost of cold chain transportation and storage. Therefore, it is of great significance to develop a lung-specific mRNA delivery platform with excellent stability.

Recently, Li Jianfeng’s research group from the University of Shanghai for Science and Technology (USST) published a research paper entitled “Helper-Polymer Based Five-Element Nanoparticles (FNPs) for Lung-Specific mRNA Delivery with Long-Term Stability after Lyophilization” in the journal Nano Letters.

The research team developed a five-element nanoparticles (FNPs) delivery platform based on helper-polymer poly (β-amino esters) (PBAEs).

The delivery platform can not only achieve efficient delivery of mRNA lung targeting, but also can be stored stably at 4 ℃ for at least 6 months after freeze-drying.

The research of Li Jianfeng’s research group is devoted to eliminating many unstable factors of LNP-mRNA drug preparations. First of all, freeze-drying technology was used to remove water molecules, inhibit hydrolysis and oxidation, and reduce the risk of mRNA fragmentation. Secondly, on the basis of previous work, alkyl side chain was introduced into PBAEs, which can not only exert its own advantages such as strong nucleic acid entrapment and lysosome escape, but also increase the stability of nanoparticles through the hydrophobic interaction between alkyl side chain and other lipids in FNP.

Finally, cationic lipid DOTAP was added to FNP to make the surface potential of nanoparticles positive. On the one hand, it can specifically target the lung by adsorbing BCG, on the other hand, the increase of charge repulsion between nanoparticles can further enhance the stability of nanoparticles.

According to the above design, the research team constructed a new PBAEs library with different capping groups, side chain length, and degree of polymerization, proving the feasibility of the combination of the three strategies to enhance stability and the universality of plasmid DNA delivery, and exploring the mechanism of organ targeting and the specificity of cell delivery in the lung.