Cubosomal hydrogels have emerged as an advanced hybrid drug delivery system combining the unique nanostructured architecture of cubosomes with the bioadhesive and viscosity-enhancing properties of hydrogels. Cubosomes are bicontinuous cubic phase lipid nanoparticles capable of encapsulating hydrophilic, lipophilic, and amphiphilic drugs within their highly ordered internal structure. However, their low viscosity and limited retention at the site of application restrict their direct topical use. Incorporation into hydrogel matrices overcomes these limitations by improving formulation stability, residence time, spreadability, and patient compliance. This review provides a comprehensive overview of cubosomal hydrogels, including their structural characteristics, composition, preparation techniques, and physicochemical evaluation parameters. The synergistic interaction between lipid nanocarriers and polymeric gel networks is discussed in detail, highlighting its influence on drug release kinetics, permeation enhancement, and therapeutic performance. Various formulation approaches and characterization methods such as particle size analysis, entrapment efficiency, rheological assessment, in vitro drug release, and ex vivo permeation studies are critically summarized. Furthermore, the therapeutic applications of cubosomal hydrogels in dermatological disorders, wound healing, antifungal therapy, anti-inflammatory treatment, and transdermal drug delivery are analyzed. Despite significant advancements at the preclinical level, challenges related to physical stability, large-scale manufacturing, drug loading variability, and limited clinical validation remain. Overall, cubosomal hydrogels represent a promising next-generation platform for controlled and localized drug delivery. Continued research focusing on stability optimization, scalable production techniques, and clinical evaluation may facilitate their successful translation into commercial pharmaceutical products.
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