| Dec 18, 2025 |
A single-atom tweak to mRNA vaccine lipids boosts cancer immunotherapyChanging just one atom in a COVID-19 vaccine lipid redirects delivery from the liver to the spleen, improving tumor suppression in mice. |
| (Nanowerk Spotlight) The lipid nanoparticle revolutionized modern medicine when it enabled the first messenger RNA (mRNA) vaccines to reach human cells during the COVID-19 pandemic. These tiny fat-based spheres ferry fragile genetic instructions past cellular defenses, allowing the body to produce proteins that train the immune system. Yet for all their success, these delivery vehicles share a stubborn flaw: they go almost exclusively to the liver. |
| The dominant ionizable lipids in approved vaccines attract liver tissue by virtue of their chemical architecture. ALC-0315, used in the Pfizer-BioNTech shot, and SM-102, the ionizable lipid in the Moderna vaccine, both contain a nitrogen-based "head group" that attracts certain blood proteins. These proteins guide particles toward hepatocytes, the liver's main functional cells. |
| This hepatic bias works well enough for vaccines injected into muscle, where local immune responses can still develop. But for therapies that need to reach the lungs, spleen, or other organs, current formulations fall short. |
| Cancer immunotherapies would benefit enormously from delivering mRNA directly to immune-rich tissues like the spleen, where T cells congregate and coordinate attacks against tumors. Researchers have experimented with entirely new lipid scaffolds to redirect delivery. Synthetic lipids modified with imidazole groups show splenic tropism. Lipids incorporating amide-bridged architectures achieve pulmonary delivery. Ketal ester lipids like KEL12 reduce liver accumulation. |
| Yet these novel chemical structures face years of safety testing before reaching patients, and many sacrifice delivery efficiency for improved targeting. Approaches using active targeting ligands add manufacturing complexity and introduce their own regulatory hurdles. |
| The field has therefore searched for ways to tweak existing, clinically validated lipids without reinventing them wholesale. |
| A study published in Advanced Materials ("Reprogramming mRNA Delivery Tropism via Nitrogen‐To‐Sulfur Substitution in Ionizable Lipids") demonstrates that swapping a single nitrogen atom for sulfur in the head group of ALC-0315 can fundamentally shift where lipid nanoparticles accumulate in the body. The modification is about as minimal as chemistry allows. Yet it redirects delivery from the liver to the lungs. |
| More striking still, mixing the new sulfur-containing lipid with its parent compound in precise ratios produces particles that home to the spleen. |
| In tumor-bearing mice, spleen-targeted nanoparticles carrying cancer-related mRNA generated potent antitumor immunity while maintaining a favorable safety profile. The approach offers a template for programming organ selectivity into delivery systems that already have regulatory track records. |
| The researchers synthesized four sulfur-based lipids using established commercial scaffolds as starting points, then selected the most promising candidate, dubbed S-ALC-0315, for detailed study. The synthesis replaced the tertiary amine head group of ALC-0315 with a sulfonium center, where sulfur carries a permanent positive charge. |
| Structurally, the two molecules are nearly identical. The difference is confined to a single atom at the functional heart of the lipid. |
| Nanoparticles formulated with S-ALC-0315 displayed physical properties similar to those made with ALC-0315. Both types measured roughly 100 nm in diameter, encapsulated more than 85% of loaded mRNA, and formed characteristic internal structures visible under cryo-electron microscopy. In cell culture, S-ALC-0315 particles delivered fluorescently tagged mRNA into dendritic cells and kidney-derived 293T cells as efficiently as their nitrogen-based counterparts. |
| The divergence appeared in living animals. When the team injected luciferase-encoding mRNA in either formulation into mice, ALC-0315 particles produced strong luminescent signal in the liver. S-ALC-0315 particles, by contrast, lit up the lungs almost exclusively. |
| Surface charge measurements hinted at one reason for this shift. The sulfonium lipid's permanent positive charge raised the apparent acid-dissociation constant of the nanoparticle surface to roughly 10.25, compared with about 6.6 for ALC-0315. Prior work has linked higher surface charge to altered protein adsorption and different organ destinations. |
| The investigators then explored what happens when both lipids occupy the same particle. They prepared nine formulations spanning molar ratios from pure ALC-0315 to pure S-ALC-0315. As the sulfur lipid fraction rose, targeting shifted progressively from liver to spleen to lung. |
| At a 2:1 molar ratio of ALC-0315 to S-ALC-0315, the particles concentrated in the spleen. They achieved mRNA expression levels there comparable to what ALC-0315 particles produce in the liver. Digital polymerase chain reaction confirmed that actual mRNA copy numbers in splenic tissue matched the imaging results. |
| Proteomic analysis of the protein "corona" that forms around nanoparticles in blood plasma suggested how organ selectivity might arise. Liver-targeting particles adsorbed high levels of apolipoproteins and complement proteins. Lung-targeting particles attracted coagulation factors and immunoglobulins. Spleen-targeting particles showed enrichment for albumin and beta-glycoprotein 1, both previously implicated in splenic delivery. The researchers acknowledge that definitive causal links remain to be established through knockout mouse experiments. |
| Spleen targeting proved especially valuable for cancer immunotherapy. In mice bearing E.G7-OVA lymphoma tumors, three intravenous doses of spleen-directed ovalbumin mRNA vaccine slowed tumor growth more effectively than either ALC-0315 or S-ALC-0315 particles alone. Flow cytometry revealed that the spleen-targeted formulation induced the highest infiltration of antigen-specific cytotoxic T cells into tumors. |
| A second tumor model used CT26 colon cancer cells engineered to overexpress Trop2, a clinically relevant tumor antigen found on breast, lung, pancreatic, and other cancers. Spleen-targeted Trop2 mRNA vaccines again outperformed alternatives, generating robust T-cell responses and pronounced tumor suppression. An ELISPOT assay, a technique that measures immune cell activity by detecting secreted proteins, confirmed superior antigen-specific immunity in mice receiving the 2:1 formulation. |
| The 2:1 formulation also retained the highest immunogenicity when administered via intramuscular injection, the route used for approved mRNA vaccines. Imaging showed that intramuscular delivery achieved robust splenic expression and markedly higher signal in draining lymph nodes compared to ALC-0315 particles alone. |
| Safety evaluations revealed no significant hemolysis, cytotoxicity, or organ damage across all tested formulations. Serum biochemistry markers for liver, kidney, and cardiac function remained within normal ranges. Cytokine surges resolved within 24 hours. Histopathology of major organs showed no structural abnormalities. |
| The practical appeal of this strategy lies in its simplicity. Rather than designing entirely new lipid families that require extensive toxicology studies, the nitrogen-to-sulfur swap preserves the bulk of ALC-0315's structure and, presumably, much of its established safety profile. Manufacturing teams can adjust mixing ratios to select the desired organ target using the same core components. |
| By altering a single atom, this research team has begun to reprogram the body's internal delivery system, routing mRNA vaccines away from the liver and toward immune-rich tissues where they may prove most effective against cancer. |
By
Michael
Berger
– Michael is author of four books by the Royal Society of Chemistry:
Nano-Society: Pushing the Boundaries of Technology (2009),
Nanotechnology: The Future is Tiny (2016),
Nanoengineering: The Skills and Tools Making Technology Invisible (2019), and
Waste not! How Nanotechnologies Can Increase Efficiencies Throughout Society (2025)
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