Luteolin stabilized in nanosheet and cubic γ-cyclodextrin-based metal organic framework for enhanced bioavailability and anti-inflammatory therapy

• Enhanced luteolin encapsulation achieved 21% loading efficiency in two variant of γ-cyclodextrin-MOFs • Optimized pH conditions significantly improved luteolin stability and encapsulation efficiency. • LT/MOFs maintained >90% drug content after 120 days under different conditions. • LT-loaded MOFs showed 6-fold higher bioavailability compared to pure luteolin. • LT/MOF formulations exhibited 4.86- and 5.4-fold higher efficacy in a rat paw edema model. Luteolin (LT), a biologically active flavonoid with potent anti-inflammatory properties, faces significant limitations due to its instability, poor absorption, and low bioavailability. To overcome these challenges, this study explores the encapsulation of LT within nanosheet and cubic γ-cyclodextrin-based metal-organic frameworks (N-MOF and CD-MOF). This approach achieved a two-fold improvement in LT loading efficiency compared to previously reported methods. A critical finding was the identification of pH as a key factor in optimizing the loading process, which significantly enhanced encapsulation efficiency. The resulting LT/N-MOF and LT/CD-MOF formulations demonstrated improved photo-stability and thermal stability, alongside significantly enhanced cellular permeation. In vitro studies revealed remarkable anti-inflammatory properties of these formulations. Moreover, the bioavailability of LT was increased by 6-fold compared to pure luteolin. In a rat paw edema model, the optimized LT/CD-MOF and LT/N-MOF formulations exhibited 4.86- and 5.4-fold improvements in anti-inflammatory activity, respectively, over pure luteolin. These results underscore the potential of CD-MOFs as effective delivery systems for enhancing the therapeutic efficacy of luteolin. Graphical representation of luteolin incorporation into cubic and nanosheet cyclodextrin-based MOFs, enhancing encapsulation, stability, bioavailability, and anti-inflammatory activity.