Lyotropic Liquid Crystals in Drug Delivery Systems

Lyotropic liquid crystals are self-assembled structures formed when amphiphilic lipids or surfactants organise into ordered mesophases in the presence of water. These mesophases—ranging from lamellar to bicontinuous cubic and hexagonal—offer internal networks of aqueous channels and lipid bilayers that can encapsulate drugs of varying solubility, molecular weight and polarity. By tuning lipid composition, hydration level and temperature, it is possible to control the geometry and dimensions of these internal channels, achieving sustained or stimuli-responsive release profiles. Such systems have demonstrated biocompatibility, low toxicity and versatility in routes of administration, including oral, parenteral and topical delivery. Emerging strategies harness responsive lipids, polymer coatings or in situ gelation to enhance targeting, mucoadhesion and circulation time. Despite challenges in large-scale manufacturing and long-term stability, advances in characterisation and formulation design are rapidly translating these soft nanostructures into clinical and veterinary applications, from anticancer therapies to treatments for chronic inflammatory and neurodegenerative disorders.

Research from Nature Portfolio

Three-dimensional cryo-electron tomography has resolved the internal architecture of dispersed bicontinuous cubic nanoparticles, revealing perfect gyroid-like networks of water channels separated by lipid bilayers and interlamellar attachments at the particle periphery. This insight has prompted a reassessment of molecular transport mechanisms and guided the engineering of more efficient release matrices. High-resolution microscopy under flow conditions has directly observed fusion events between cubosome nanocarriers and supported lipid bilayers, demonstrating that fusion kinetics and extent depend on the lipid composition of both the carrier and the target membrane. These findings clarify how nanocarrier design influences cellular uptake and payload delivery. In parallel, the creation of ultra-swollen bicontinuous cubic mesophases with water channels up to five times larger than traditional systems has expanded the size range of encapsulable macromolecules and opened new possibilities for sustained release of large therapeutic proteins and complex biologics.

Lyotropic Liquid Crystals in Drug Delivery Systems publication trend

The graph below shows the total number of articles in lyotropic liquid crystals in drug delivery systems across all publications each year (not limited to Nature Index journals).

Technical terms

Lyotropic liquid crystal: A phase formed by amphiphilic molecules in a solvent, exhibiting both fluidity and long-range order.

Cubosome: A nanoparticle of bicontinuous cubic phase stabilised by amphiphilic polymers or surfactants, featuring internal aqueous channels.

Bicontinuous cubic phase: A periodic three-dimensional structure in which two continuous aqueous networks intertwine within a lipid bilayer matrix.

Hexagonal phase: A lyotropic mesophase comprising cylindrical lipid assemblies organised in a hexagonal lattice, creating rod-like aqueous channels.

Mucoadhesion: The property of a material to adhere to mucosal tissues, prolonging residence time and enhancing local drug absorption.

References

1. Lipidic lyotropic liquid crystals: Insights on biomedical applications. Advances in Colloid and Interface Science (2023).
2. Direct visualization of dispersed lipid bicontinuous cubic phases by cryo-electron tomography. Nature Communications (2015).
3. Fusion dynamics of cubosome nanocarriers with model cell membranes. Nature Communications (2019).
4. Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains. Nature Communications (2018).
5. An injectable in situ gel with cubic and hexagonal nanostructures for local treatment of chronic periodontitis. Drug Delivery (2017).
6. Advances in the Design of pH-Sensitive Cubosome Liquid Crystalline Nanocarriers for Drug Delivery Applications. Nanomaterials (2020).
7. Theranostic combinatorial drug-loaded coated cubosomes for enhanced targeting and efficacy against cancer cells. Cell Death & Disease (2020).
8. Cubic Liquid Crystalline Nanostructures Involving Catalase and Curcumin: BioSAXS Study and Catalase Peroxidatic Function after Cubosomal Nanoparticle Treatment of Differentiated SH-SY5Y Cells. Molecules (2019).