A multifunctional curcumin–Fe ₃ O ₄ @ZIF-8 nanoformulation as a <i>T</i> ₂ MRI contrast agent and pH-responsive theranostic platform for targeted ROS generation, radiosensitization, and triple-negative breast cancer t

Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant malignancies, necessitating the development of innovative therapeutic approaches. Here, we report a multifunctional theranostic nanoformulation (curcumin-Fe₃O₄@ZIF-8) integrating MRI-guided imaging, pH-responsive drug release, radiosensitization, and reactive oxygen species (ROS)-induced apoptosis into a single platform. Fe₃O₄@ZIF-8 nanoparticles (NPs) served as a T₂-weighted MRI contrast agent, achieving <i>r</i>₂ relaxivity values of 25.14 mM^-1 s^-1 at pH 5.5 and 14.65 mM^-1 s^-1 at pH 7.4, demonstrating pH-responsive contrast enhancement for improved tumor imaging. The ZIF-8 shell enabled tumor-specific curcumin release, with ∼75% drug release at pH 5.5 (tumor microenvironment) <i>versus</i> only ∼45% at pH 7.4 within 48 h, ensuring minimal systemic toxicity. Cellular uptake studies in MDA-MB-231 cells confirmed dose-dependent internalization, with 84.3% nanoparticle uptake at 100 μg mL^-1. Importantly, ROS generation increased by 28.6% at pH 5.5, thereby amplifying oxidative stress and inducing apoptosis. <i>In vitro</i> cytotoxicity assays revealed that Cur-Fe₃O₄@ZIF-8 reduced MDA-MB-231 cell viability by 72.4% at 48 h, with an IC₅₀ of 98.86 μg mL^-1, compared to 293.8 μg mL^-1 for Fe₃O₄@ZIF-8, thus demonstrating an ∼3-fold enhancement in therapeutic potency. Furthermore, X-ray radiotherapy (2 Gy) in combination with Cur-Fe₃O₄@ZIF-8 further reduced the IC₅₀ to 80.37 μg mL^-1, underscoring its radiosensitization capabilities. Cell cycle analysis revealed G2/M-phase arrest, contributing to impaired cancer cell proliferation. Apoptosis assays confirmed a significant increase in early and late apoptotic populations, while real-time PCR analysis showed significant downregulation of anti-apoptotic BCL-xL and cyclin D1 genes with considerable upregulation of pro-apoptotic BAX, thus reinforcing the mechanism of tumor suppression. This triple-action theranostic system surpasses conventional chemotherapy and standalone MRI contrast agents by combining precision imaging with targeted therapy, offering transformative advancement in TNBC treatment.