Mechanistic insights into drug loading, host-guest interactions, and release in cyclodextrin-based metal-organic...

Cyclodextrin-based metal-organic frameworks (CD-MOFs) combine molecular host cavities with framework-generated porosity, but their rational use in drug delivery requires clearer links between guest localization, host-guest interactions, and release. This critical narrative review integrates experimental and computational evidence for native α-, β-, and γ-CD-MOFs, distinguishing them from modified, composite, and MOF-derived carriers. A claim-specific evidence hierarchy separates spatially resolved observations, indirect experimental support, and computational inference. Guest localization depends on molecular dimensions, ionization, polarity, aperture accessibility, loading level, and processing history. Different loadings can favor distinct occupancy patterns, surface association, or guest-rich domains; these comparative states do not establish dynamic redistribution without time-resolved evidence. Stabilization generally involves cooperative hydrogen bonding, hydrophobic and dispersion interactions, and electrostatic or cation-associated contributions. Release may reflect framework transformation or dissolution, diffusion through persistent or added barriers, host-guest dissociation, and subsequent complexation, aggregation, or recrystallization. Similar release profiles can therefore arise from different mechanisms. A diagnostic framework links release interpretation to carrier persistence, guest speciation, medium chemistry, and analytical sampling, while source-specific loading definitions constrain quantitative comparisons. Molecular simulations provide candidate configurations and pathways but require experimental validation; kinetic fits alone do not identify microscopic release mechanisms. This synthesis establishes a structure-occupancy-transport framework and identifies the paired structural, time-resolved, and solution-state measurements needed for more predictable CD-MOF-based drug delivery.