Drug-in-Cyclodextrin-in-Liposome Hybrid Systems for Hydrophobic Drug Delivery: A Comprehensive Review.

Delivering hydrophobic active pharmaceutical ingredients remains a major challenge due to poor aqueous solubility, limited bioavailability, and chemical instability. Drug-in-cyclodextrin-in-liposome (DCL) technology combines cyclodextrin inclusion complexation with liposomal encapsulation to address these limitations. In this hybrid approach, the hydrophobic drug is first incorporated into the apolar cyclodextrin cavity, and the resulting complex is subsequently encapsulated within the aqueous compartment of liposomes. This review provides a comprehensive, data-driven analysis of DCL technology, covering its conceptual development, cyclodextrin properties, lipid composition, vesicle architecture, and preparation methods. Quantitative parameters, including encapsulation efficiency, particle size, zeta potential, and drug release, are compared with conventional liposomes and cyclodextrin complexes. DCL systems demonstrated 2 to 11 fold higher encapsulation efficiency than conventional liposomes, together with sustained release, improved vesicle stability, and enhanced protection of labile drugs against degradation. Preclinical evidence indicates potential therapeutic benefits, although in vivo validation remains limited. Molecular docking and molecular dynamics further provide mechanistic insights into drug-cyclodextrin and cyclodextrin-membrane interactions. Emerging strategies include surface modification, stimuli-responsive systems, dual-drug loading, green manufacturing, and computational design, supporting the future clinical translation of DCL technology.