In silico development of an inflammation-triggered β-cyclodextrin carrier for a redox-active vanadium-INAP-tryptophan...

Inflammation-driven diseases are characterized by localized oxidative stress, acidosis, and hyperthermia-microenvironmental features that often compromise the effectiveness of conventional anti-inflammatory therapies due to poor site selectivity and uncontrolled systemic exposure. In this context, the present study provides an exclusively in silico investigation of an inflammation-responsive drug delivery concept based on β-cyclodextrin (β-CD) encapsulation of a redox-active vanadium complex, VO-INAP-tryptophan. Leveraging the supramolecular host-guest properties of β-CD, the computational model explores a system designed to remain stable under physiological conditions while undergoing selective destabilization within the pathological microenvironment of inflamed tissues. Two plausible inclusion modes of the vanadium complex within the β-CD cavity were systematically evaluated under simulated inflammatory conditions, including acidic pH, increased dielectric constant, and elevated temperature. Frontier molecular orbital analysis and global reactivity descriptors were used to examine how variations in electronic structure, thermodynamic stability, and chemical reactivity influence encapsulation strength and release propensity. The results identify a specific inclusion conformation particularly susceptible to solvent competition and electronic destabilization, indicating a favorable pathway for site-selective release. Component-resolved electronic analysis highlights the complementary roles of the vanadium center and the tryptophan ligand in modulating redox behavior and potential anti-inflammatory activity. Overall, this study provides computational insights that may inform a mechanistic framework for designing inflammation-responsive supramolecular delivery systems and suggests the potential of β-cyclodextrin architectures for optimizing the therapeutic performance of redox-active metal complexes, pending experimental validation.