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.

中文翻译：

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用于 mRNA 传递的脂质聚合物杂化纳米材料。

介绍

在过去的十年中，信使 RNA (mRNA) 在各种生物医学应用中得到了广泛的探索。然而，mRNA的有效传递仍然是其在临床广泛应用的关键挑战之一。最近，脂质聚合物杂化纳米粒子（LPN）正在发展成为一类有前途的 RNA 递送生物材料，它整合了脂质和聚合物的物理化学特性。我们之前开发了一种N ¹ , N ³ , N ⁵ -三(2-氨基乙基)苯-1,3,5-三甲酰胺(TT)衍生的类脂纳米材料(TT3-LLN)，它能够有效地传递多种类型的mRNA。为了进一步提高TT3-LLN的递送效率，在本研究中，我们重点研究了掺入不同聚合物对建立LPN的影响，旨在开发一种优化的脂质聚合物杂化纳米材料，用于高效的mRNA递送。

方法

我们将一系列可生物降解和生物相容性的聚合物材料融入到TT3-LLN的配方中来开发LPN。评估了不同LPN的mRNA递送效率，并进一步进行了系统的正交优化。

结果

我们的数据表明，与其他聚合物相比，PLGA4（MW 24,000–38,000 g/mol）显着提高了 TT3-LLN 的递送效率。进一步优化确定 PLGA4-7 LPN（PLGA:mRNA = 9:1，质量比；TT3:DOPE:Cholesterol:DMG-PEG ₂₀₀₀  = 25:25:45:0.75，摩尔比）作为先导制剂，显示出显着增强与 TT3-LLN 相比，在三种不同的人类细胞系中传递两种类型的 mRNA。

结论

这项研究的结果可能为开发用于基于 mRNA 的疗法的 LPN 提供新的见解。