Recently, messenger ribonucleic acid (mRNA) therapy represents a novel approach for treating a wide range of diseases, encompassing both immune-related and non-immune conditions. However, successful translation of mRNA medicines into clinical applications remains limited, probably due to the efficiency and targeting ability of delivery systems. While lipid nanoparticles (LNPs) have become the leading delivery vehicle, optimizing their liver-targeting ability through chemical modifications remains a key scientific challenge.

Breakthrough Research Design

A study titled "Deciphering the Role of PEGylation on the Lipid Nanoparticle-Mediated mRNA Delivery to the Liver," published in ACS Nano by Professor Jianjun Cheng's team at Westlake University, systematically investigated the multifacial role of PEGylated lipids in manipulating LNP-mediated delivery of mRNA to the liver. It reveals that the hydrophilic-lipophilic balance and terminal modification of PEGylated lipids are directly related to LNP de-PEGylation, which in turn influences the in vitro and in vivo delivery efficiency.

The study employs a multidimensional evaluation system (Figure 1):

• In vitro: De-PEGylation rate, cellular uptake, endosomal escape, transfection efficiency

• In vivo: Mononuclear phagocyte system (MPS) clearance rate, pharmacokinetics, biodistribution, liver subcellular targeting

Figure 1. Schematic Illustration of the Chemical Structure of PEGylated Lipids and Their Impact on LNP Performance

The researchers selected five types of PEGylated lipids with different structures, maintaining a fixed molar ratio of 1.5% and a PEG molecular weight of 2000 Da. By varying the hydrophilic-lipophilic properties (single alkyl chain, dual alkyl chains, and different alkyl chain lengths) and terminal groups (such as methoxy, carboxyl, and amino) of the PEGylated lipids, they investigated the impact on LNP-mediated liver delivery (Figure 2). Experimental results showed that the structure of PEGylated lipids significantly affects liver delivery efficiency and can be correlated with the de-PEGylation rate.

Figure 2. Relationship Between PEGylated Lipid Structure and De-PEGylation Rate.

Key Findings:

De-PEGylation Rate Determines Targeting Fate (Figure 3)

• Ultra-fast De-PEGylation (SA-PEG): Accelerates blood clearance and promotes LNP accumulation in Kupffer cells (liver immune cells).

• Moderate De-PEGylation (DMG-PEG): Balances circulation time and liver cell targeting, enhancing mRNA expression in liver parenchymal cells.

• Stable coating (DSPE-PEG): Prolongs blood circulation but significantly reduces liver deposition efficiency.

Figure 3. Impact of De-PEGylation Rate on LNP Pharmacokinetics and Biodistribution.

2.Terminal Group "Fine-Tuning" Leads to Efficiency Leap (Figure 4)

Replacing the PEG terminal group from methoxy to carboxyl (-COOH) or amino (-NH₂) accelerates De-PEGylation and enhances interactions between LNPs and liver cells, resulting in a 2- to 3-fold increase in mRNA delivery efficiency to the liver.
This finding offers a new perspective on "chemical modification as an alternative to complex formulation screening."

Figure 4. Impact of PEGylated Lipid Terminal Group Modifications on In Vivo LNP Delivery Efficiency.

3. Cell Type-Specific Delivery (Figure 5)

By modulating the PEG structure, the researchers achieved targeted delivery of LNPs across different liver cell types:

SA-PEG LNPs: Preferentially accumulate in Kupffer cells, comprising 68% of liver deposition.

DMG-PEG LNPs: Enhance delivery efficiency to hepatocytes by 40%.

Figure 5. Effect of PEGylated Lipids on LNP Delivery to Liver Subcellular Targets.

This study comprehensively reveals the multifaceted roles of PEGylated lipids in LNP-mediated mRNA liver delivery, offering new insights for optimizing LNP design. Future research will further explore the interactions between PEGylated lipids and ionizable lipids, aiming to enhance mRNA delivery efficiency through structural modulation of PEGylated lipids. It is hoped that this work will deepen the understanding of the critical role of PEGylated lipids in mRNA delivery and provide valuable references for the design of LNPs targeting specific organs.
Huateng Pharma is a trusted supplier of high-purity PEG linkers, which are crucial for the development of lipid nanoparticle (LNP) drug delivery systems. With a focus on quality and precision, Huateng Pharma provides a wide range of PEG derivatives from milligram to kilogram quantities, all produced under strict GMP standards, such as mPEG-DSPE, mPEG-DMG, PEG-NH2, PEG-Acid, to support various applications such as gene therapy and mRNA delivery. 

References:
Gao, M.; Zhong, J.; Liu, X.; Zhao, Y.; Zhu, D.; Shi, X.; Xu, X.; Zhou, Q.; Xuan, W.; Zhang, Y.; Zhou, Y.; Cheng, J.Deciphering the Role of PEGylation on the Lipid Nanoparticle-Mediated mRNA Delivery to the Liver. ACS Nano, 2024 https://doi.org/10.1021/acsnano.4c09399