Cubosome-based skin delivery: from topical to transdermal applications.

INTRODUCTION: Skin delivery provides an alternative drug administration, although its effectiveness is limited by the stratum corneum barrier. Cubosomes, as third-generation lipid nanoparticles with bicontinuous cubic liquid crystalline structures, have emerged as promising nanocarriers that enhance skin penetration, sustain drug release, improve bioavailability, and minimize toxicity. AREAS COVERED: This review discusses the biopharmaceutical mechanisms of cubosome-mediated skin delivery, including bioadhesion, stratum corneum lipid fluidization, controlled release, enhanced cellular uptake, and improved bioavailability. Literature from 2006-2026 was collected from Scopus, PubMed, and patent databases, covering localized applications such as dermatological disorders, wound healing, fungal infections, alopecia, inflammatory skin diseases, and oncology, as well as systemic therapies including rheumatoid arthritis, gout, diabetes mellitus, and hormone replacement therapy. Recent advances, including microneedle integration, thermosensitive hydrogels, stimuli-responsive systems, and surface-engineered cubosomes, are also highlighted. EXPERT OPINION: Cubosomes represent a promising platform for advanced skin delivery. Optimal performance depends on the therapeutic goal, with systemic delivery requiring enhanced permeation and sustained absorption, whereas localized therapy prioritizes intradermal retention and tissue depot formation with minimal systemic exposure. Despite strong preclinical evidence, further studies on long-term safety, manufacturing standardization, and clinical validation are essential for successful clinical translation and commercialization of cubosome-based skin delivery.