A Zn(II)-coordinated calix[8]arene azocarboxylate metal–organic nanocarrier for efficient drug delivery

Supramolecular and metal-coordinated nanocarriers have recently gained significant attention as advanced platforms to enhance the therapeutic index of anticancer agents. Herein, we report, to the best of our knowledge, the first Zn(II)-coordinated metal–organic nanocomposite derived from a carboxylic acid-functionalized calix[8]arene azo scaffold (CAC8A@Zn), engineered as a high-performance drug delivery system. The rational design integrates the electron-rich, π-conjugated cavity of calix[8]arene with Zn(II) coordination nodes, enabling synergistic enhancement of host–guest interactions, structural integrity, and drug encapsulation efficiency. The resulting CAC8A@Zn nanocomposite demonstrates an exceptionally high doxorubicin (DOX) loading capacity (90 ± 4.75%) alongside favorable physicochemical characteristics. Structural and morphological analyses, including AFM, SEM, PXRD, and DLS, confirm the formation of a uniform, crystalline porous nanostructure with well-defined nanoscale architecture. Hydrodynamic diameter measurements revealed mean sizes of 304.6 ± 4.5 nm for CAC8A@Zn and 362.1 ± 4.5 nm upon DOX loading, indicating successful drug incorporation. Biological evaluations highlight the excellent biocompatibility of the carrier, as evidenced by high viability in 3T3 fibroblasts and negligible hemolytic activity toward human erythrocytes. Importantly, DOX-loaded CAC8A@Zn exhibits significantly enhanced cytotoxicity against MCF-7, HepG2, and H1299 cancer cell lines compared to free DOX and non-metalated CAC8A, while reducing off-target effects. Density functional theory (DFT) calculations further elucidate the molecular basis of drug–carrier interactions, revealing energetically favorable binding modes that underpin the high loading efficiency and sustained release behavior. Collectively, this study introduces a novel metal–organic calixarene-based nanocarrier with a rationally engineered supramolecular architecture, supported by combined experimental and theoretical insights. The CAC8A@Zn system represents a versatile and scalable platform for next-generation chemotherapeutic delivery with improved efficacy and safety profiles.