Abstract
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-b10 LLNs, a lead material, increasing delivery efficiency over 2-fold. More importantly, pegylated TNT-b10 LLNs is stable for over four weeks and is over 10-fold more efficient than that of its counterpart TNT-a10 LLNs. Additionally, the optimal formulation O-TNT-b10 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.
Highlights
Lipid-like nanoparticles (LLNs) have shown great potential for RNA delivery
Among the wide variety of these systems, lipid- and polymer-based nanomaterials have been reported for mRNA delivery[25,26,27,28,29,30]
In order to investigate the effects of structural transformation of lipid-like compounds on mRNA delivery efficiency, we designed and synthesized TNT-b8 to TNT-b14
Summary
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. Each component is necessary to form stable nanoparticle formulations, lipid-like compounds, consisting of amino groups and multiple lipid tails, play a significant role for efficient delivery of RNA11. We previously reported a series of lipid-like 1,3,5-triazinane-2,4,6-trione (TNT) derivatives consisting of a six-membered ring and three lipid tails, among of which TNT-a10 shows efficient delivery of siRNA (Fig. 1B)[15]. In order to investigate the effects of local structural transformation of lipid-like compounds on messenger RNA delivery, we report the synthesis of lipid-like compounds TNT-b8 to TNT-b14 and their delivery efficiency of mRNA (Fig. 1A). We studied delivery efficiency of the optimized TNT-b10 LLNs (O-TNT-b10 LLNs) in vivo through three administration routes including intravenous (i.v.), intraperitoneal (i.p.), and subcutaneous (s.c.)
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