A single LNP dose achieved 49% liver gene editing in mice — without viral vectors

Key Findings

🧠 Brain tumor mRNA delivery — 9.9x better accumulation in mice

• Mannose-cholesterol lipid nanoparticles (MC_LNPs) accumulated 9.9-fold more in the brains of healthy mice compared to non-targeted formulations, suggesting meaningful blood-brain barrier penetration.

• In mice with glioblastoma (an aggressive brain tumor), MC_LNPs loaded with PTEN mRNA (a tumor-suppressing gene) reduced tumor burden 6-fold and extended median survival from 33 to 49 days.

• The key innovation: mannose-cholesterol conjugation achieved ~30 mol% surface ligand density — high enough to compete with blood glucose for GLUT1 (a sugar transporter abundant on brain blood vessels and overexpressed in glioblastoma), something conventional methods couldn't reach.

🦠 A dual-antigen mRNA vaccine clears hepatitis B virus in mice

• A two-antigen mRNA vaccine combining preS1 and HBsAg (two surface proteins from the hepatitis B virus) led to near-complete viral genome clearance and serological conversion in chronic HBV mouse models.

• preS1 drove the T cell response against HBV, while HBsAg contributed to antibody production and boosted immune cell activation — the two antigens appear to work through complementary mechanisms.

• Adding interferon-α (IFN-α) to the vaccine regimen further improved antiviral effectiveness and immune memory, while maintaining a favorable safety profile in the mouse models tested.

💉 Spleen-targeted LNPs hit an 85.88 spleen-to-liver expression ratio

• Lipid nanoparticles built with hydroxylated-linker ionizable lipidoids achieved a spleen-to-liver mRNA expression ratio of up to 85.88 — a sharp contrast to conventional LNPs, which predominantly accumulate in the liver.

• The linker structure of the ionizable lipidoid (the key charged component of the LNP) turned out to be a critical variable: hydroxylated linkers outperformed alkylated and esterified versions for both cellular uptake and spleen selectivity.

• Using this platform, researchers developed an mRNA vaccine targeting EBV-associated cancers (like certain lymphomas), leveraging the spleen's natural role as an immune activation hub — and the PEG-free design may reduce some known safety concerns around PEGylated particles.

🦟 100% protection against malaria in mice with a dual-antigen mRNA vaccine

• The vaccine construct Mal05 (encoding two P. falciparum antigens — PfCSP and PfRH5 — in a single tandem mRNA) conferred 100% sterile protection (meaning no detectable infection) in mice challenged with a transgenic malaria parasite expressing PfCSP.

• Mal05 induced high-titer, durable antibodies capable of blocking both sporozoite invasion (the liver stage) and red blood cell infection (the blood stage) in lab tests, plus strong CD4⁺ and CD8⁺ T cell responses.

• The vaccine was delivered using lipid-polyplex (LPP) nanoparticles — a hybrid of lipid and polymer components — rather than standard LNPs.

🌬️ A natural plant compound boosted inhaled mRNA vaccine response 14.95x in mice

• Incorporating acacetin (a natural flavonoid compound) as a fifth component into inhaled LNPs increased lung transfection by 10.82-fold in mice compared to standard formulations.

• Mice receiving acacetin-LNPs loaded with SARS-CoV-2 spike mRNA produced 14.95x higher IgG (blood antibodies) and 2.38x higher IgA (mucosal antibodies, important for respiratory protection) than those receiving conventional LNPs — with no detected toxicity.

• Mechanistically, acacetin appeared to reshape the intracellular environment in lung cells by activating antioxidant pathways and dampening pro-inflammatory signaling, which may have supported higher mRNA translation.

🔬 A new mRNA stability model cut prediction error by more than 2x

• A four-feature regression model called STRAND achieved a greater than 2-fold reduction in prediction error for mRNA in-solution stability compared to existing machine learning and deep learning approaches.

• The key addition: base-pairing log odds (LO), a fine-scale measure of local RNA structure, provided information that global metrics like minimum free energy (MFE) missed — the two types of features appear to be complementary rather than redundant.

• mRNA stability in solution matters for vaccine shelf life and storage — RNA degrades primarily through hydrolysis, and secondary structure (how the RNA folds) protects against this; better stability predictions could inform sequence design earlier in development.