A Curcumin‐Loaded Iron‐Porphyrin Covalent Organic Framework Alleviates Atherosclerosis by Modulating Oxidative Stress and Lipid Metabolism

ABSTRACT Atherosclerosis (AS) requires multi‐target therapies addressing lipid accumulation, oxidative stress, and inflammation, yet lipid‐lowering alone insufficiently mitigates residual cardiovascular risk. Curcumin (Cur), a natural polyphenol with well‐established anti‐atherosclerotic activities, is severely hampered by extremely low oral bioavailability and rapid metabolic clearance. To overcome these limitations, an iron porphyrin‐based covalent organic framework (COF), FeTAPP‐Dha, was prepared by condensing 5,10,15,20‐tetrakis‐(4‐aminophenyl)‐porphyrin‐Fe‐(III) chloride with 2,5‐dihydroxyterephthalaldehyde. Cur was then incorporated into the hydrophobic channels of FeTAPP‐Dha through hydrogen‐bond‐mediated size matching, producing FeTAPP‐Dha‐Cur with a loading efficiency of 12.5%. The incorporated iron porphyrin units provide reactive oxygen species scavenging capability, enabling sustained H 2 O 2 decomposition and intercepting oxidative stress at its source. Moreover, the acidic microenvironment characteristic of atherosclerotic plaques impairs hydrogen‐bonding interactions, facilitating on‐demand Cur release at lesion sites while minimizing systemic exposure. In ApoE −/− mice, FeTAPP‐Dha‐Cur effectively inhibited foam cell formation and significantly reduced aortic plaque burden. These effects were accompanied by activation of the AMP‐activated protein kinase–acetyl‐CoA carboxylase signaling axis and suppression of inflammation. Collectively, FeTAPP‐Dha‐Cur achieved superior therapeutic outcomes compared with free Cur or empty carrier. This work establishes a COF‐based synergistic platform that integrates carrier‐mediated microenvironment regulation with stimuli‐responsive drug delivery, offering a promising paradigm for multi‐target AS therapy.