pH‐Sensitive Metal–Organic Frameworks for the Improved Inhibition of HepG2 Cell via Folate Receptor‐Mediated Targeting and Cascaded CDT Effect

ABSTRACT Metal–organic frameworks (MOFs) have great potential for the development of targeted drug delivery systems (DDSs) to improve the effectiveness of inhibiting HepG2 cells. Herein, inspired by the solvothermal synthesis method and the concept of designable assembly, MOF (UiO‐66‐NH 2 ) is first doped by Fe‐Cu NPs to form Fe‐Cu@MOF and further modified with polydopamine (PDA) and folic acid (FA) to obtain Fe‐Cu@MOF‐PDA‐FA for the loading of resveratrol (RES). The Fe‐Cu@MOF‐PDA‐FA has desirable drug loading efficiency and excellent pH‐responsive release of RES. In vitro cellular experiments and 3D hepatoma cell microspheres model, the Fe‐Cu@MOF‐PDA‐FA not only showed low cytotoxicity but also post‐drug has a good inhibitory effect on HepG2. In addition, Fe‐Cu@MOF‐PDA‐FA could achieve good tumor penetration via FR‐mediated endocytosis, while showing good anticancer cellular activity and the ability to promote reactive oxygen species (ROS) generation. Therefore, RES@Fe‐Cu@MOF‐PDA‐FA has promising applications as pH‐responsive DDS in combination with chemodynamic therapy (CDT) for cancer therapy.