Spin‐Density‐Guided Rational Design of High‐Performance Ferroptosis Theranostics

Ferroptosis is driven by Fe 3+ accumulation and subsequent lipid peroxidation, which exacerbates tissue degeneration. However, current interventional materials rarely achieve synergistic efficient iron chelation and real‐time in vivo monitoring of degeneration, largely due to insufficient mechanistic understanding at the electronic structure level. Here, a quantum chemistry–guided strategy is proposed for designing ferroptosis theranostic materials by regulating molecular binding energy ( ΔE bind ) and integrated spin density ( ISD ), enabling effective Fe 3+ removal and simultaneous magnetic resonance imaging (MRI). Density functional theory (DFT) calculations were combined with in vitro MRI to systematically correlate the electronic structure characteristics of different iron chelates with their magnetic resonance responses. The results reveal that when ΔE bind < −5.8 eV and ISD < 3.2 ℏ/2, iron chelators not only exhibit strong Fe 3+ binding but also effectively attenuate Fe 3+ paramagnetism, leading to significantly enhanced T 2 ‐MRI contrast. Guided by these criteria, a multifunctional controlled‐release microsphere, termed HAMA@PPDG, was constructed for osteoarthritis (OA) theranostics. In a ferroptosis‐related OA model, HAMA@PPDG alleviated cartilage degeneration, improved tissue structure, and enhanced matrix preservation, while enabling dynamic visualization of degenerative progression by T 2 ‐MRI. Overall, this work establishes quantum chemistry‐guided electronic‐structure design principles for ferroptosis theranostic materials, providing a new paradigm for precise intervention in ferroptosis‐related pathologies.