Repurposing mesalamine via peptide-functionalized zeolitic imidazolate framework-8 (ZIF-8) nanoparticles for selective breast cancer targeting.

Breast cancer treatment continues to be limited by insufficient tumor selectivity and adverse systemic effects, highlighting the need for delivery systems that improve drug accumulation in malignant cells while minimizing exposure to healthy tissue. In this study, we designed an integrin-targeting nanosystem for drug repurposing by encapsulating mesalamine (MES) within a zeolitic imidazolate framework-8 nanocarrier (nZIF-8) and functionalizing the surface with an Arg-Gly-Asp (RGD) peptide via one-pot synthesis. The MES-RGD@nZIF-8 nanocarriers showed high encapsulation efficiency (99.69%) and preserved the structural and morphological characteristics of ZIF-8 following functionalization. Release studies demonstrated controlled MES diffusion at physiological pH and accelerated release under mildly acidic conditions, consistent with ZIF-8 degradation. Biological evaluation showed that MES-RGD@nZIF-8 induced 65% cytotoxicity at 48 h, outperforming free MES and non-targeted formulations. The elevated selectivity index (SI = 4.53) demonstrated preferential cytotoxicity toward breast cancer cells compared with normal cells, confirming the enhanced tumor selectivity of the formulation. Molecular docking simulations revealed that the presence of RGD in the nZIF-8 framework enhanced the binding affinity of MES by providing greater interaction sites compared to the pristine nZIF-8. These findings demonstrate that RGD-functionalized nZIF-8 is a promising platform for targeted drug repurposing in breast cancer therapy.