Researchers at the Innovation Center of NanoMedicine and collaborators have shown that a transient coating applied to the inner walls of liver sinusoids can sharply reduce the unintended uptake of mRNA lipid nanoparticles by the liver in mice. The coating agent, a positively charged oligopeptide linked to two polyethylene glycol (PEG) chains, adsorbs to the sinusoidal endothelium for only a few hours before being excreted, leaving liver function intact. The study was published in ACS Nano.
When mRNA therapies are delivered via lipid nanoparticles — whether intravenously, intramuscularly, or by direct tumor injection — a large fraction accumulates in the liver. This off-target accumulation can cause unwanted protein production, potential hepatitis, and reduced delivery to immune-rich organs such as the spleen that are critical for vaccine efficacy.
In live-mouse imaging experiments, pre-administration of the coating agent suppressed liver accumulation of intravenously injected lipid nanoparticles. Protein expression from the mRNA in the liver dropped several dozenfold, while expression in the spleen rose severalfold, indicating that particles diverted from the liver reached the spleen instead.
The team tested the approach across three mRNA therapeutic categories. For an intramuscular COVID-19 spike-protein vaccine, the coating reduced hepatic spike-protein production — a risk factor for vaccine-associated hepatitis and possible immune tolerance — without lowering antibody induction and with enhanced cellular immunity.
In a cancer-vaccine model using intravenous delivery targeting the spleen, the coating strengthened the cellular immune response essential for anti-tumor activity, attributed to improved spleen protein expression.
For cancer cytokine therapy, where mRNA encoding immune-activating cytokines is injected directly into tumors, the coating curtailed cytokine production in the liver and its systemic spillover, preserving therapeutic efficacy while lowering toxicity risk.
The coating agent is already in clinical trials for oligonucleotide delivery to tumors, and its safety profile has been established in those studies, supporting faster translation to mRNA applications.
The researchers conclude that transient sinusoidal shielding addresses a major practical bottleneck for lipid-nanoparticle-based mRNA vaccines and immunotherapies, offering a broadly applicable strategy to improve both safety and targeting.
Temporary liver coating may improve safety and targeting of mRNA vaccines and cancer therapies
This is an independent summary. The complete reporting, supporting context and any primary documents remain with Phys.org.