Metal–Organic Framework DNA Hydrogel Microspheres Enable Ferroptosis-Based Therapy for Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) remains a challenging malignancy due to limited therapeutic efficacy of conventional chemotherapy, which is often hampered by drug resistance and systemic toxicity. Ferroptosis, an iron-dependent regulated cell death mechanism, has emerged as a promising strategy for cancer treatment. Curcumin, a natural compound with demonstrated anticancer properties, faces significant clinical translation barriers due to its poor solubility and bioavailability. To address these challenges, we developed a tumor microenvironment-responsive nanogel microsphere (MCCH) system using DNA hydrogel and metal-organic framework (MOF) technology for codelivery of curcumin and cisplatin. We comprehensively evaluated the MCCH system's physicochemical properties, drug release profiles, and cytotoxicity. In vitro and in vivo experiments were conducted to assess its capacity for ferroptosis induction, malignant phenotype suppression, and tumor growth inhibition. The MCCH system demonstrated ATP-triggered drug release and potent ferroptosis induction in ESCC cells, as evidenced by glutathione depletion, accumulation of lipid peroxidation, and modulation of GPX4/ACSL4 expression pathways. In vivo studies showed significant reduction of tumor volume and inflammatory markers while maintaining low systemic toxicity. The MCCH system not only enhances curcumin's delivery efficiency but also synergizes with cisplatin to trigger ferroptosis through dual modulation of GPX4/ACSL4 pathways. This innovative approach represents a promising targeted therapy for ESCC with substantial clinical translational potential.