ACS nanoSep 3, 2026

Temporary Liver Lining Shielding by 2-arm-PEG-Oligocations Reduces Unwanted mRNA Nanoparticle Delivery in the Liver

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 4, 2026

Abstract

Hepatic protein expression from ionizable lipid nanoparticles (iLNPs) was reduced by more than 10-fold using a stealth-coating strategy in mouse models.

Stealth-coating the liver sinusoidal endothelial wall with a specific material may enhance the safety of mRNA-based vaccines by limiting off-target effects.
The coating method preserved iLNP accumulation in the spleen, a crucial target for vaccine delivery.
Preinjection of the stealth-coating improved vaccine efficacy while reducing concerns about liver antigen expression.
In cytokine mRNA therapy, this approach successfully decreased off-target expression of interleukin-12 in the liver without compromising its antitumor effects.
These findings suggest that targeting the LSE wall could be a viable strategy for enhancing the performance of iLNPs in therapeutic applications.

Simplified

Ionizable lipid nanoparticles (iLNPs) are powerful platforms for mRNA-based vaccines and immunotherapies; however, their intrinsic liver tropism compromises both safety and efficacy. Off-target hepatic protein expression from delivered mRNA raises safety concerns, and hepatic clearance limits efficient iLNP delivery to target organs. In this study, we address these challenges in mouse models by stealth-coating the liver sinusoidal endothelial (LSE) wall, the primary gateway for nanoparticle entry into the liver. Specifically, oligocations conjugated with two-armed PEG (2-arm-PEG-oligocations), a clinically relevant material used in oligonucleotide delivery trials, were employed to transiently anchor PEG to the LSE wall with balanced affinity, ensuring robust coating followed by gradual biliary clearance. This approach reduced hepatic protein expression from iLNPs, subsequently administered either systemically or locally, by more than 10-fold. Importantly, the strategy preserved iLNP accumulation in the spleen, a key target organ for vaccines, effectively redirecting iLNPs from the liver to the spleen. Consequently, in vaccine applications, preinjection of the 2-arm-PEG-oligocation preserved or even enhanced vaccination efficacy while minimizing concerns associated with antigen expression in the liver. In applications involving cytokine mRNA therapy, specifically intratumoral interleukin-12 (IL-12) mRNA administration, systemic preinjection of the 2-arm-PEG-oligocation successfully reduced off-target hepatic IL-12 expression and subsequent systemic IL-12 exposure, while maintaining antitumor efficacy. Collectively, these results demonstrate that LSE-wall stealth coating is a generalizable strategy to improve both the safety and efficacy of iLNP-based mRNA vaccines and immunotherapies.

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Temporary Liver Lining Shielding by 2-arm-PEG-Oligocations Reduces Unwanted mRNA Nanoparticle Delivery in the Liver

Abstract

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