Reversible Fe ³⁺ Coordination Drives Polydopamine Nanoparticle Assembly for High Iron Loading and Ferroptosis Selectivity

Polydopamine (PDA) nanomaterials are widely studied as biodegradable carriers for metal ions, particularly Fe³⁺, due to the strong affinity of catechol groups for iron. However, generating very small PDA nanoparticles with a high iron-loading capacity remains difficult. Here, we show that polymerizing dopamine at low concentration in alkaline buffer yields very small PDA nanoparticles (sPDA, ∼4 ± 2 nm) that rapidly assemble into nanoagglomerates (∼120 nm) upon exposure to Fe³⁺ (sPDA-Fe). These sPDA-Fe assemblies can accommodate high iron content (∼30 wt % Fe) and remain colloidally stable for days without the need for additional capping ligands. We further show that the reversible formation of sPDA-Fe is driven by coordination with Fe³⁺, as the nanoagglomerates readily disassemble in the presence of metal chelators. Finally, we demonstrate that sPDA-Fe nanoagglomerates can be utilized to deliver iron into four human cancer cell lines with distinct metabolic phenotypes. Unlike free iron, sPDA-Fe induces a dose-dependent loss of viability, consistent with ferroptotic cell death triggered by lipid peroxidation. Cell line-specific differences in pyroptotic or apoptotic signaling are also detected. Overall, sPDA-Fe acts as an efficient and tunable iron-delivery platform with a high loading capacity that can initiate iron-dependent cell death and may enable therapeutic applications targeting iron-sensitive mechanisms.