Advances in Cubosome-Based Transdermal Delivery: Structural Design, Manufacturing, and Engineering Strategies.

Cubosomes are third-generation lipidic nanocarriers characterized by bicontinuous cubic liquid-crystalline nanostructures and exceptionally high internal surface areas. These architectures enable the encapsulation of hydrophilic, hydrophobic, and amphiphilic compounds while providing enhanced stability, cargo protection, and controlled drug release. Their ordered nanostructure, governed by lipid self-assembly and critical packing parameter principles, promotes an effective interaction with the stratum corneum, making cubosomes promising transdermal delivery platforms. This review summarizes the physicochemical principles, fabrication technologies, and engineering strategies underlying cubosome-based transdermal systems. Specific crystallographic mesophases are influenced by lipid composition, stabilizers, guest molecules, and fabrication conditions, which determine the structural integrity and delivery performance. Despite their advantages, conventional cubosomes still exhibit limitations, including high bulk viscosity, burst release, inadequate deep dermal penetration, phase instability, and limited long-term stability. To overcome these challenges, advanced approaches including chemical phase modulation, hybrid integration with microneedles or hydrogels, surface functionalization, and stimuli-responsive systems are discussed. Emerging technologies such as microfluidics, quality by design, process analytical technology, artificial intelligence/machine learning-assisted optimization, and smart personalized transdermal drug delivery systems are also highlighted for next-generation cubosome development. These integrated strategies improve skin permeation, formulation stability, therapeutic efficacy, and manufacturing scalability while supporting the future translational development of cubosome-based nanomedicines for transdermal administration of small molecules and biomacromolecular therapeutics.