Double coordination-driven Fe-DOX synergy enhances ferroptosis and immunogenic cancer therapy

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a potential therapeutic strategy for cancer. However, intrinsic resistance, off-target toxicity, and poor redox efficiency limit the effectiveness of existing ferroptosis-inducing platforms. This study reports novel heparin-derived metal coordination nanoparticles (HDMC NP) that leverage catechol-metal-drug coordination chemistry to enhance ferroptosis and immunogenic cell death (ICD). In this self-assembled supramolecular system, doxorubicin (DOX) directly coordinates to Fe³⁺ centers established by catechol-Fe³⁺ interactions on the heparin backbone, forming a stable HDMC NP with high drug-loading efficiency. This coordination not only stabilizes the complex under neutral conditions but also triggers disassembly in response to pH changes in the tumor microenvironment. Notably, the DOX-Fe³⁺ pairing supports sustained redox activity, amplifying ROS production and ferroptotic stress in a coordination-dependent manner beyond the effect of either component alone. In animal models, HDMC NP suppresses tumor growth by inducing both ferroptosis and ICD, characterized by calreticulin exposure and CD8⁺ T cell infiltration. Collectively, this platform provides a redox-active nanotherapeutic based on coordination-defined assembly with potential for broad applications in metal-ion modulated diseases.