This study presents an innovative nanocomposite designed to enhance gene and drug delivery for cancer treatment. The nanocomposite consists of (NH₂)-MIL-125(Ti), a metal–organic framework (MOF) conjugated with poly(aniline-co-para-phenylenediamine), and coated on manganese ferrite nanoparticles (MnFe₂O₄). This composite is used to co-deliver the chemotherapy drug doxorubicin (DOX) and plasmid CRISPR (pCRISPR) to cancer cells. The study investigates whether surface modification with amine groups can improve cellular uptake and transfection efficiency. Additionally, an engineered cell-imprinted substrate is used to mimic the cellular environment and enhance the delivery and expression of edited genes. Key findings include: 1. **Reliable Platform for Multi-Drug Delivery**: The (NH₂)-MIL-125(Ti)/poly(aniline-co-para-phenylenediamine)/MnFe₂O₄ nanocomposite successfully co-delivers DOX and pCRISPR, indicating its potential for combination cancer therapy. 2. **Hemocompatibility**: Hemolysis analysis revealed less than 1% hemolysis, suggesting biosafety. 3. **Enhanced Cellular Uptake**: Amine surface modification increased cellular uptake by up to 38.3% in A549 cells, improving transfection efficiency. 4. **Enhanced Therapeutic Efficacy**: The cell-imprinted substrate enhanced therapeutic efficacy by promoting delivery and expression in a physiologically relevant microenvironment. Overall, this study makes significant contributions to gene delivery and expression for cancer therapy, demonstrating the potential of the engineered nanocomposite, amine surface modification, and cell-mimetic substrate to augment the efficacy of combination gene and drug therapy against cancer.This study presents an innovative nanocomposite designed to enhance gene and drug delivery for cancer treatment. The nanocomposite consists of (NH₂)-MIL-125(Ti), a metal–organic framework (MOF) conjugated with poly(aniline-co-para-phenylenediamine), and coated on manganese ferrite nanoparticles (MnFe₂O₄). This composite is used to co-deliver the chemotherapy drug doxorubicin (DOX) and plasmid CRISPR (pCRISPR) to cancer cells. The study investigates whether surface modification with amine groups can improve cellular uptake and transfection efficiency. Additionally, an engineered cell-imprinted substrate is used to mimic the cellular environment and enhance the delivery and expression of edited genes. Key findings include: 1. **Reliable Platform for Multi-Drug Delivery**: The (NH₂)-MIL-125(Ti)/poly(aniline-co-para-phenylenediamine)/MnFe₂O₄ nanocomposite successfully co-delivers DOX and pCRISPR, indicating its potential for combination cancer therapy. 2. **Hemocompatibility**: Hemolysis analysis revealed less than 1% hemolysis, suggesting biosafety. 3. **Enhanced Cellular Uptake**: Amine surface modification increased cellular uptake by up to 38.3% in A549 cells, improving transfection efficiency. 4. **Enhanced Therapeutic Efficacy**: The cell-imprinted substrate enhanced therapeutic efficacy by promoting delivery and expression in a physiologically relevant microenvironment. Overall, this study makes significant contributions to gene delivery and expression for cancer therapy, demonstrating the potential of the engineered nanocomposite, amine surface modification, and cell-mimetic substrate to augment the efficacy of combination gene and drug therapy against cancer.