An Acid-Activated Graphene Oxide Ferroptosis Rheostat for Plaque-Targeted Atherosclerosis Therapy

<title>Abstract</title> <p> Background Atherosclerotic plaques contain acidic, iron-rich niches in which lipid peroxidation and inflammation reinforce one another. Single-pathway interventions are therefore unlikely to restore local redox balance. We developed GO@Drug, a graphene oxide (GO) nanoplatform that co-delivers quercetin and β-sitosterol to modulate ferroptosis and inflammation within plaques. Results Under acidic conditions, GO catalysed Fe ³⁺ reduction to Fe ²⁺ , creating a localized redox input. Quercetin engaged the AKT1-GPX4 antioxidant pathway, whereas β-sitosterol suppressed IL-1β-driven inflammatory signaling, together restoring redox homeostasis in macrophage foam cells. Catalytic attenuation of GO, AKT1 knockout, or IL-1β reconstitution weakened the therapeutic response, confirming contributions from both the material and the loaded drugs. In ApoE-/- mice, GO@Drug accumulated in plaques, reduced lesion burden, increased fibrous cap thickness, and restored ferroptosis-associated redox balance without detectable systemic toxicity. Plaque-specific Fe ²⁺ imaging and radiolabel tracking further showed local activation and gradual clearance. Conclusions These findings identify GO as an active redox modulator and support a microenvironment-responsive strategy for controlling ferroptosis-inflammation coupling in atherosclerosis. </p>