Fibronectin‐Functionalized Tea Polyphenol Nanoparticles Loaded with Ferrostatin‐1 for Synergistic Abdominal Aortic Aneurysms Therapy

Abstract Abdominal aortic aneurysm (AAA) is a life‐threatening cardiovascular condition with complex pathophysiology, for which effective pharmacological treatments are currently lacking. Recently, ferroptosis has been identified as a key mechanism of vascular smooth muscle cell (VSMC) death, emerging as a potential therapeutic target for mitigating aortic aneurysms. Here, a drug‐delivery nanoparticle system combining tea polyphenol‐based nanoparticles and a ferroptosis inhibitor is developed. This system, formed through the oxidative polymerization and self‐assembly of epigallocatechin gallate (EGCG), efficiently encapsulates Ferrostatin‐1 (Fer‐1) during self‐assembly and is subsequently functionalized with fibronectin (FN) for targeted treatment of angiotensin II‐induced AAA. Both in vitro and in vivo experiments demonstrated that TPN‐Fer‐1@FN effectively inhibits ferroptosis, suppresses the inflammatory response, and reduces matrix degradation, while preserving the normal contractile function of VSMCs and modulating the NOTCH3 signaling pathway. Moreover, the TPN‐Fer‐1@FN nanosystem exhibited low toxicity and good biocompatibility. These findings suggest that TPN‐Fer‐1@FN represents a promising therapeutic strategy for inhibiting ferroptosis and modulating the pathological processes underlying AAA.