Small (Weinheim an der Bergstrasse, Germany)Sep 21, 2026

How PEG-Lipid Structure Controls Zinc-Dependent Movement of mRNA-Carrying Nanoparticles to the Spleen

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 22, 2026

Abstract

Zn²⁺ addition leads to a concentration-dependent shift in mRNA expression from the liver to the spleen in LNP formulations.

The PEG₁₆ formulation showed a more pronounced redistribution of mRNA expression compared to the conventional PEG_2k formulation.
Zn²⁺ is linked to protein-corona changes, particularly increasing levels of apolipoprotein H, which is associated with targeting the spleen.
Reduced inflammatory transcriptional activation was observed in response to Zn²⁺ incorporation.
In a tumor model, treatment with Zn@PEG₁₆-LNP improved tumor control and enhanced immune responses, indicated by higher IgG and CD8⁺ T-cell activity.
These results suggest that the structure of PEG-lipid interfaces and Zn²⁺ incorporation could be effective for directing mRNA delivery to the spleen.

Simplified

PEG-lipid interfaces influence LNP nano-bio interactions, yet conventional PEG-lipid formulations differ simultaneously in several molecular features that complicate attribution of ion-dependent effects. Here, using structurally defined DMA-PEG₁₆-OMe as a discrete PEG-lipid model and conventional DMA-PEG_2k-OMe as a comparator, we show that Zn²⁺ addition produces a concentration-dependent redistribution of organ-associated LNP-mediated mRNA expression from the liver toward the spleen. This redistribution was most pronounced in the PEG₁₆ formulation and was not observed to the same extent in the conventional PEG_2k formulation, supporting PEG-lipid interfacial architecture as an important determinant of the Zn²⁺-dependent response. Mechanistically, Zn²⁺ is associated with protein-corona remodeling, including enrichment of apolipoprotein H (ApoH; β₂-glycoprotein I), a corona component previously linked to splenic tropism, together with reduced inflammatory transcriptional activation. In a prophylactic B16F10-OVA-luc challenge model, Zn@PEG₁₆-LNP treatment was associated with improved tumor control, higher total serum IgG and IgG1 signals, and stronger SIINFEKL-responsive CD8⁺ T-cell responses. Together, these findings identify PEG-lipid interfacial architecture and Zn²⁺ incorporation as a simple formulation strategy for spleen-directed mRNA delivery.

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How PEG-Lipid Structure Controls Zinc-Dependent Movement of mRNA-Carrying Nanoparticles to the Spleen

Abstract

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