Gene therapy holds great promise as a therapeutic approach for combating cancer, with the choice of gene delivery vector being a critical factor in its success. In recent years, metal–organic frameworks (MOFs) have emerged as valuable tools for intracellular plasmid delivery in this field. This study aimed to encapsulate plasmid DNA encoding the TP53 tumor suppressor gene (pEGFP-N1-TP53) within zeolitic imidazolate framework-8 (ZIF-8) MOFs and ZIF-8-PEI. Subsequently, the transfection efficiency and ability to induce cell death were assessed in MDA-MB-231, MCF-7, and HeLa cancer cells. A comparative analysis was conducted to evaluate the induction of cell death by pEGFP-N1-TP53@ZIF-8-PEI, pEGFP-N1-TP53-ZIF-8 nanoparticles, and Lipofectamine in the aforementioned cell lines. Additionally, an optimal condition for loading the plasmid into ZIF-8 was proposed. The findings from cell transfection assays, MTT assay, and flow cytometry revealed that both pEGFP-N1-TP53@ZIF-8-PEI and pEGFP-N1-TP53-ZIF-8 effectively delivered the plasmid to the cells. Notably, pEGFP-N1-TP53@ZIF-8-PEI exhibited significant results, inducing 77% cell death in the HeLa cell line and 73% in the MDA-MB-231 cell line. Our observations indicated that MDA-MB-231 and HeLa cells exhibited heightened responsiveness to TP53 gene therapy when delivered through ZIF-8-PEI and ZIF-8. Based on these findings, further investigation of pEGFP-N1-TP53@ZIF-8-PEI as a potential cancer therapeutic platform in other cancer cell types is warranted.
