EDTA-Functionalized Nanoscale Metal-Organic Framework for Onco-Cardiology via Radiochemotherapy Synergy and Spatiotemporally Matched Iron Chelation.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) has become a major obstacle for clinical application. While ferroptosis represents a critical therapeutic target for DIC, current intervention strategies are limited by spatiotemporal mismatches between DOX accumulation and iron chelation. Here, we engineered an EDTA-functionalized Hf-based metal-organic framework for DOX delivery. This nanoplatform (DME) simultaneously mediates tumor radiochemotherapy synergy and inhibits ferroptosis via real-time iron chelation in cardiac tissue. The EDTA modification not only enhances drug penetration to kill deep-seated tumors, but also endows DME superior iron-scavenging ability, which effectively suppresses mitochondrial-dependent ferroptosis in cardiomyocytes. Using primary cultured neonatal mice cardiomyocytes and a chronic DIC murine model, we demonstrated DME's significant cardioprotection and elucidated its mechanistic basis. Thus, our work establishes a bifunctional nanoplatform that unifies oncotherapy and cardioprotection, offering a spatiotemporally matched iron-chelation strategy for safe and effective clinical use of DOX.