Ceramide EOS in bicelles: Biophysical implications for membrane organization

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Ceramides play crucial roles in membrane function and structure. Ceramide EOS (CerEOS) is essential in forming the skin intercellular lipid lamellae and its absence causes an impaired skin barrier, leading to skin disorders such as Autosomal Recessive Congenital Ichthyoses. Despite its biological relevance, CerEOS' biophysical impact in phospholipid membranes remains poorly understood. These critical insights are particularly relevant in the design of new therapeutic lipid-based formulations aimed at restoring barrier function. The present work examines how CerEOS, an ultra-long chain acylceramide, and Ceramide IIIB (CerIIIB), a medium-chain ceramide, modulate the properties of phospholipid bilayers. Using bicelles as a model nanosystem, we specifically address how the incorporation of those ceramides affects bicelle size, morphology, thermotropic behavior and phospholipid membrane organization. Ten bicellar systems were prepared with DPPC or DMPC, DHPC, and CerEOS or CerIIIB in two different concentrations. DLS and CryoTEM analyses revealed that ceramide chain length and concentration crucially impact bicelles morphology, as well as the structure of the bicellar system, with CerEOS inducing bicelle stacking and more pronounced nanostructural changes. DSC, SAXS and WAXS measurements showed that ceramide incorporation increases thermotropic complexity and bicelle thickness due to the formation of ceramide enriched domains. CerEOS promotes the formation of different membrane domains and disordered lateral packing symmetries. Notably, this is the first study to examine the effects of CerEOS in phospholipid-based bicelles. Our findings highlight the importance of chain length mismatch and hydrogen bonding in lipid organization, and demonstrate that bicelles offer a robust platform for elucidating ceramide-phospholipid interactions.

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