Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

Lipid-like nanoparticles (LLNs) have shown great potential for RNA delivery. Lipid-like compounds are key components in LLNs. In this study, we investigated the effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Our results showed that position change of functional groups on lipid-like compounds can dramatically improve delivery efficiency. We then optimized formulation ratios of TNT-b(10) LLNs, a lead material, increasing delivery efficiency over 2-fold. More importantly, pegylated TNT-b(10) LLNs is stable for over four weeks and is over 10-fold more efficient than that of its counterpart TNT-a(10) LLNs. Additionally, the optimal formulation O-TNT-b(10) LLNs is capable of delivering mRNA encoding luciferase in vivo. These results provide useful insights into the design of next generation LLNs for mRNA delivery.