With the rising incidence of cancer, chemotherapy has become a widely used treatment approach. However, the use of anticancer drugs such as doxorubicin (DOX) poses significant long-term risks due to its nonspecific distribution and severe side effects. Therefore, developing a nanoparticle-based drug delivery system (DDS) that enhances the bioavailability of DOX specifically to cancer cells is crucial while minimizing its side effects on normal cells. This study employed zeolitic imidazolate framework-8 (ZIF-8) as a DDS to encapsulate DOX using a one-pot method. The surface of this system was subsequently modified with a copper-gallic acid (Cu-GA) complex to form the Cu-GA/DOX@ZIF-8 (CGDZ) system. The CGDZ system effectively encapsulates DOX and demonstrates pH-responsive drug release, facilitating controlled drug release in the acidic environment of cancer cells. Furthermore, the Cu-GA coating enhances the biocompatibility of the material, reduces drug toxicity in normal endothelial cells (BAECs) due to the antioxidant feature of modified GA, and maintains the efficacy and intracellular trafficking of DOX in colon cancer cells (C-26). Interestingly, CGDZ nanoparticles showed significantly higher toxicity against cancer cells as compared to unmodified systems and free DOX. Overall, CGDZ exhibited significant