Using humanized liver mice to advance the development of LNP delivery systems

Non-viral delivery systems, such as lipid nanoparticles (LNP), are driving the next wave of nucleic acid therapeutics by enabling efficient intracellular delivery of mRNA and siRNA, including gene-editing payloads in clinical settings. LNP offer scalable manufacturing, tunable biodistribution, and favorable safety profiles compared with viral vectors, making them a cornerstone of next-generation therapeutics. Although LNP delivery is the basis for a number of clinically approved products, challenges remain for enabling future LNP delivery systems. One critical factor is the identification of appropriate preclinical models to test the efficacy and toxicity of LNP-based therapeutics at an early stage of development, as this can have a big impact on the chances of the therapeutic making it to market. 

Using humanized liver mice to advance the development of LNP delivery systems

Burmeister et al. · Nucleic Acid Insights 2026; 3(8), 233–242 · DOI: 10.18609/nai.2026.030

What you will learn

01

Why mouse models poorly predict LNP behaviour in humans

02

How PXB-mice recapitulate human liver physiology

03

How humanized mice catch human-specific hepatotoxicity

The preclinical workflow

1

LNP formulation & IV dosing

2

IHC payload expression

3

Serum biomarkers & biochemistry

4

Species-specific gene silencing

Key findings

Dose-dependent mRNA expression in human hepatocytes; well tolerated up to 5 mg/kg

siRNA-LNP selectively silenced human TTR without affecting mouse TTR

Detected human-specific hepatotoxicity of ALN-HBV and gapmers missed by rodent and NHP models

LNP efficacy in PXB-mice matched NHP responses, supporting use as a cost-effective screening alternative

Key interests

LNP delivery

mRNA therapeutics

Preclinical models

Hepatotoxicity

Gene silencing

Humanized mice

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