Engineered (NH2)-MIL-125(Ti)/copolymer@MnFe2O4 nanocomposite for synergistic eradication of cancer cells via DOX/pCRISPR delivery

Abstract The present study proposed an innovative nanocomposite aimed at enhancing gene and drug delivery for cancer treatment. The nanocomposite was composed of amine-functionalized metal–organic frameworks, (NH 2 )-MIL-125(Ti), conjugated to poly(aniline- co -para-phenylenediamine), and coated on manganese ferrite nanoparticles that were utilized to co-deliver the chemotherapy drug doxorubicin (DOX) and plasmid CRISPR (pCRISPR) to cancer cells. The investigation focused on whether surface modification with amine groups could improve cellular uptake and transfection efficiency. In addition, the study also utilized an engineered cell-imprinted substrate to mimic the cellular environment and enhance the delivery and expression of edited genes. The results demonstrated the proposed nanocarriers successfully co-delivered DOX and pCRISPR, indicating their potential for combination cancer therapy. Specific highlights include (1) reliable platform for multi-drug delivery based on the (NH 2 )-MIL-125(Ti)/poly(aniline- co -para-phenylenediamine)/MnFe 2 O 4 nanocomposite structure; (2) hemocompatibility analysis revealed less than 1% hemolysis, pointing to biosafety; (3) amine surface modification enhanced cellular uptake up to 38.3% in A549 cells, improving transfection; (4) 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. The engineered nanocomposite, amine surface modification, and cell-mimetic substrate employ innovative strategies to augment the efficacy of combination gene and drug therapy against cancer. Graphical Abstract