Triterpenoids Bend and Bind Lipid Membranes into 20 nm Stable Nanocages

Achieving a small size without compromising structural stability remains a key challenge in liposome design. Liposomes below 50 nm penetrate barriers more effectively but suffer from curvature-driven instabilities. Here, we introduce a plant-derived triterpenoid as a dual-function molecular modulator that enables the formation of ultrasmall (≈20 nm), thermochemically stable lipid nanocages. Mechanistically, it induces positive membrane curvature to accommodate a small size while reinforcing bilayer cohesion through interlipid hydrogen bonding. This molecular 'glue' effect stabilizes the membrane under extreme curvature, decoupling the classical size-stability trade-off. Molecular dynamics simulations and experiments confirm that this structural remodeling imparts enhanced resistance to heat, pH, and surfactant disruption─conditions that typically destabilize conventional liposomes. These insights suggest potential therapeutic applications, including improved transdermal penetration and preliminary indications of enhanced epidermal regeneration.