Lipid Polymer Hybrid Nanomaterials for mRNA Delivery

Introduction: In the past decade, messenger RNA (mRNA) has been extensively explored in a wide variety of biomedical applications. However, efficient delivery of mRNA is still one of the key challenges for its broad applications in the clinic. Recently, lipid polymer hybrid nanoparticles (LPNs) are evolving as a promising class of biomaterials for RNA delivery, which integrate the physicochemical properties of both lipids and polymers. We previously developed an N¹,N³,N⁵-tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (TT) derived lipid-like nanomaterial (TT3-LLN) which was capable of effectively delivering multiple types of mRNA. In order to further improve the delivery efficiency of TT3-LLN, in this study, we focused on studying the effects of incorporating different polymers on establishing LPNs and aimed to develop an optimized lipid polymer hybrid nanomaterial for efficient mRNA delivery. Methods: We incorporated a series of biodegradable and biocompatible polymer materials into the formulation of TT3-LLNs to develop LPNs. mRNA delivery efficiency of different LPNs were evaluated and a systematic orthogonal optimization was further carried out. Results: Our data indicated that PLGA4 (MW 24,000–38,000 g/mol) dramatically increased delivery efficiency of TT3-LLNs in comparison to other polymers. Further optimization identified PLGA4-7 LPNs (PLGA:mRNA = 9:1, mass ratio; TT3:DOPE:Cholesterol:DMG-PEG₂₀₀₀ = 25:25:45:0.75, molar ratio) as a lead formulation, which displayed significantly enhanced delivery of two types of mRNA in three different human cell lines as compared with TT3-LLNs. Conclusions: Results from this study potentially provide new insights into developing LPNs for mRNA based therapeutics.