Nanoscale localisation of memantine governs structural modulation and loading in bicontinuous cubic phase systems

Memantine is a primary pharmacological treatment for moderate-to-severe Alzheimer's disease but its efficacy and brain delivery remain limited. Lipid bicontinuous cubic phases and their nanoparticle dispersions (cubosomes) offer platforms for enhancing central nervous system drug delivery, yet the rigid adamantane scaffold of memantine can destabilise lipid organisation. This study resolves how an amphiphilic, adamantane-containing drug interacts with non-lamellar lipid bilayers using monoolein-based bulk cubic mesophases and cubosomes formulated with biomimetic lipid compositions and multiple stabilisers. SAXS revealed that lipid composition primarily governed mesophase structure, while memantine induced only modest structural changes in bulk cubic phases. Following memantine incorporation, cubosomes retained cubic symmetry and colloidal stability across stabilisers, although they were more susceptible than bulk phases to additive-induced disorder, with cryo-TEM showing transitions toward less ordered, lower curvature sponge-like structures. Bulk mesophases exhibited 3-5-fold higher apparent drug retention than nanoparticle dispersions. Under excess hydration, however, even bulk phases released memantine rapidly, losing ∼65% of the drug within 24 h. SANS and molecular dynamics simulations revealed a mobile state of memantine with predominantly interfacial localisation rather than stable burial within the hydrophobic tails, providing a mechanistic explanation for its mesophase-dependent structural effects and its limited retention. These findings show that the adamantane scaffold alone is insufficient to ensure efficient incorporation into cubic phases. Localisation, accommodation, and retention are governed by the balance between hydrophobic anchoring and the hydration demands of attached functionalities, establishing a mechanistic framework for predicting the behaviour of amphiphilic adamantane-containing therapeutics in non-lamellar lipid nanocarriers.