Lipid-based crystalline materials have been proposed as controlled drug delivery systems. Differences in liquid crystal nanostructure have previously been shown to change drug diffusion and hence release, however there has been little progress towards the use of in situ changes to nanostructure to control drug release. In this study, phytantriol and glyceryl monooleate-based bicontinuous cubic and inverse hexagonal nanostructures have been designed to allow change to the nanostructure in response to external change in temperature, with a view to controlling drug release rates in vivo. Changes to nanostructure with temperature were confirmed by crossed polarized optical microscopy and small angle X-ray scattering. Phytantriol containing 3 (w/w) vitamin E acetate provided the necessary phase transition behavior to progress this system to in vitro release and in vivo proof of concept studies. Using glucose as a model hydrophilic drug, drug diffusion was shown to be reversible on switching between inverse hexagonal and bicontinuous cubic nanostructures at temperatures above and below physiological temperature respectively. An in vivo proof of concept study in rats showed that after subcutaneous administration of these materials, the changes in nanostructure induced by application of a heat or cool pack at the injection site stimulated changes in drug release from the matrix anticipated from in vitro release behavior, thereby demonstrating the potential utility of these systems as on demand drug release delivery vehicles.