Cubosomes in non-oral drug delivery: Advancing precision therapeutics from bench to bedside

Cubosomes are advanced nanostructured lipid carriers characterized by their internal bicontinuous cubic phases, which enable the simultaneous encapsulation of both hydrophilic and lipophilic therapeutics. Their unique architecture imparts superior bioadhesion, sustained drug release, and enhanced mucosal and transdermal permeability, making them promising candidates for non-oral drug delivery. This review provides a comprehensive analysis of cubosome design strategies, fabrication methodologies, and functional performance across various administration routes, including transdermal, ocular, pulmonary, parenteral, and intranasal. Comparative evaluations demonstrate that cubosomes consistently outperform conventional nanocarriers-such as liposomes and solid lipid nanoparticles-in terms of encapsulation efficiency, release kinetics, and therapeutic outcomes. Noteworthy advances include their application in brain-targeted delivery, localized chemotherapeutic regimens, and antifungal pulmonary therapy. Emerging translational efforts, such as clinical studies involving statin-loaded cubosomal gels for periodontitis, further underscore their clinical promise. Despite these advancements, challenges persist regarding large-scale production, regulatory standardization, and comprehensive toxicity assessment. Nevertheless, recent innovations in microfluidic fabrication, surface modification, and stimuli-responsive systems continue to propel the field forward. This review highlights the evolving landscape of cubosome-based therapeutics and outlines key opportunities for their integration into next-generation, patient-centric drug delivery platforms.