Cyclic-thiourea ionizable lipids program multilamellar mRNA-LNPs for sustained expression, frozen-storage stability and potent vaccine immunotherapy

Lipid nanoparticles (LNPs) have become essential for mRNA therapeutics delivery; however, their transient expression and unstable formulation limit their wider use. Scientists have now discovered a lipid nanoparticle (HI-62) that has ionizable properties, featuring a 1,3,5-triazinane-2-thione headgroup. This new design allows for consistent assembly of mRNA into onion-like multilamellar nanoparticles.

Cryo-electron microscopy showed the ordered internal lamellae structure, while molecular dynamics simulations supported a cooperative assembly model driven by pH-responsive electrostatics, headgroup preorganization, and short-range directional interactions. The HI-62 formulation can maintain over 95% mRNA encapsulation, ranging from N/P ratios of 3-7. This enhances reporter expression duration significantly compared to existing formulations following intravenous or intramuscular delivery.

The stability of the HI-62 formulation is also remarkable, as it retains its physicochemical integrity and in vivo potency even after repeated freeze-thaw cycles and 18 months of storage at -20°C. In tumor models, this new LNP formulation elicits robust cellular responses and demonstrates considerable inhibition of tumor growth.

This discovery establishes cyclic-thiourea headgroup chemistry as a design principle for programming lipid-RNA organization into multilamellar architecture, providing a foundation for developing next-generation LNPs with durable protein expression and superior stability.

The HI-62-based LNP formulation is currently being used in an mRNA cancer vaccine program, which is expected to enter clinical development in the coming months.