γ-Cyclodextrin Metal-Organic Frameworks for Drug Delivery: Current Advances in Synthesis, Activation, Encapsulation...

Metal-organic frameworks (MOFs) are a versatile class of hybrid crystalline materials that have emerged as promising candidates for a broad range of applications. γ-cyclodextrin MOFs (γ-CD-MOFs) represent an innovative subgroup of MOFs constructed from "edible" γ-CD ligands coordinated with biocompatible metal ions to form an extended porous structure. Owing to their unique characteristics such as their "green" origin, biodegradability, and biocompatibility they became a promising platform for drug delivery applications. Structurally, γ-CD-MOF possess a body-centered cubic structure with dual-mode porosity, enabling the simultaneous encapsulation of hydrophilic and hydrophobic drugs. Such structural features contribute to high loading capacity, tunable release behavior, and enhanced stability of incorporated drugs. In this review, we comprehensively discuss the structural features of γ-CD-MOF, synthesis strategies, crystals size and morphology control, activation and drying techniques, and drug encapsulation approaches. We further address computational and simulation approaches used to predict and optimize drug-framework interactions, as well as post- synthetic modifications aimed at enhancing stability and functionality. The diverse pharmaceutical applications of γ-CD-MOFs are examined, including the delivery of small molecules, macromolecules, multi-drug systems, and emerging pulmonary formulations. Additionally, we examine biocompatibility and safety considerations and current limitations related to aqueous stability, industrial-scale production, and reproducibility. Finally, this review highlights recent progress and underlines future perspectives, emphasizing innovations such as fast drug-loaded MOF formation via spray-drying, co-delivery strategies, and vaccine-oriented formulations. Together, these insights highlight the potential of γ-CD-MOFs to shape the next generation of multifunctional drug delivery systems across interdisciplinary fields.