Cyclodextrin Interactions with Water-Soluble Vitamins: Biological Relevance, Stability, Delivery, and Translational Implications-A Critical Review.

Water-soluble vitamins participate in essential metabolic, redox, and coenzyme-dependent processes, yet their effective delivery can be limited by chemical instability, degradation during processing or storage, restricted membrane transport, and formulation-dependent loss of biological availability. Cyclodextrins have been widely investigated as molecular hosts and functional components of delivery systems capable of modifying these properties. This critical narrative review evaluates cyclodextrin systems involving thiamine, riboflavin, nicotinic acid and nicotinamide, pantothenate, vitamin B6 vitamers, biotin, folates, cobalamins, and vitamin C, with particular emphasis on the relationship between molecular interaction mechanisms and functional or biological outcomes. The available evidence demonstrates that cyclodextrins can protect selected vitamins against photochemical, thermal, and chemical degradation, modify release profiles, facilitate local or transdermal delivery, and support pharmaceutical, food, biomedical, and analytical applications. However, these effects cannot always be attributed to classical cavity inclusion. Depending on vitamin structure, hydration, charge, and molecular size, the underlying mechanism may involve partial inclusion, external hydrogen bonding, ion pairing, multivalent association, or physical entrapment within cyclodextrin-containing materials. Distinguishing these mechanisms is essential for interpreting whether an observed improvement in stability, permeability, or biological performance can reasonably be linked to molecular complexation. Importantly, evidence that cyclodextrin association increases systemic vitamin bioavailability in vivo remains limited, and improvements in solubility or release should not automatically be considered evidence of enhanced biological availability. Future studies should therefore integrate rigorous molecular characterization with permeability, cellular, pharmacokinetic, and in vivo evaluation. Such an approach can establish a mechanistic link between cyclodextrin-vitamin interactions and their biological and translational significance.