Positron Emission Tomography/Computed Tomography Imaging‐Guided Polydopamine Nanoparticles Attenuate Foam Cell Ferroptosis for Targeted Antiatherosclerotic Therapy

Atherosclerosis (AS) is a significant contributor to cardiovascular events. Recent studies have demonstrated that ferroptosis of foam cells is a significant driver of AS. Nevertheless, insights into the precise antiferroptosis therapies remain limited. Here, a multifunctional theranostic nanoplatform is engineered by conjugating folate-modified polydopamine (PDA) nanoparticles (NPs) with L-arginine (FPLG) to inhibit ferroptosis of foam cells. In vitro studies demonstrate that FPLG NPs effectively attenuate ferroptosis in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages by scavenging reactive oxygen species, upregulating GPX4 and NRF2 activity, and regulating lipid metabolism. In vivo, FPLG NPs exhibit preferential accumulation in atherosclerotic plaques via folate receptors (FRs)-mediated targeting and the enhanced permeability and retention effect (EPR effect), as confirmed by fluorescence imaging and chelator-free ⁶⁸Ga-labeled positron emission tomography/computed tomography (PET/CT). Treatment with FPLG NPs in ApoE^-/- mice reduces plaque area by over 40%, enhances fibrous cap stability, and mitigates ferroptosis. Transcriptomics further reveals that the FPLG treatment suppresses ferroptosis and inflammatory pathways. This dual-modality platform integrates targeted ferroptosis inhibition and real-time imaging, offering a promising strategy for precise AS management.