Abstract: Hesperetin (HES) was incorporated into the ZIF-8 framework via a one-pot method to construct HES@ZIF-8 nanocomposites. The morphology, crystal structure, pore structure, and thermal stability were systematically characterized using scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, nitrogen adsorption-desorption, and thermogravimetric analysis . Furthermore, the drug-loading capacity and in vitro release behavior under different pH conditions were evaluated . The results demonstrate the successful construction of HES@ZIF-8, which retained the regular polyhedral morphology and characteristic crystal framework of ZIF-8 after loading, indicating that the introduction of HES did not disrupt the host framework structure. Changes in pore structure parameters and thermal weight loss behavior further confirmed the effective integration of HES into the ZIF-8 system, achieving a drug-loading capacity of 72.0% . In vitro drug release studies revealed that HES@ZIF-8 exhibited a pronounced pH-dependent release profile, with cumulative release rates of 42.9%, 72.6%, and 92.9% at pH 7.4, 6.5, and 5.5, respectively. The significant dissociation of the particle framework under acidic conditions indicates that the accelerated release is closely related to the acid-induced structural disruption of ZIF-8. In vitro cellular experiments showed that HES@ZIF-8 possessed good biocompatibility with normal fibroblasts (L929) within a working concentration range of 0–40 μg/mL. Concurrently, the material decreased the viability of CAL-27 and SACC cells, inhibited cell migration, and promoted apoptosis, with a more pronounced effect observed in SACC cells . These findings indicate that HES@ZIF-8 features both structure-retaining loading and tumor microacidic environment-responsive release, providing an experimental basis for the design of natural small molecule/MOF composite smart drug delivery materials.

Key words: hesperetin, ZIF-8; metal-organic frameworks, nanocomposites, acid-responsive release