Combating Atherosclerosis with Chirality/Phase Dual‐Engineered Nanozyme Featuring Microenvironment‐Programmed Senolytic and Senomorphic Actions

Senescence plays a critical role in the development and progression of various diseases. This study introduces an amorphous, high‐entropy alloy (HEA)‐based nanozyme designed to combat senescence. By adjusting the nanozyme's composition and surface properties, this work analyzes its catalytic performance under both normal and aging conditions, confirming that peroxide and superoxide dismutase (SOD) activity are crucial for its anti‐aging therapeutic function. Subsequently, the chiral‐dependent therapeutic effect is validated and the senolytic performance of D‐handed PtPd2CuFe across several aging models is confirmed. Through multi‐Omics analyses, this work explores the mechanism underlying the senolytic action exerted by nanozyme in depth. It is confirm that exposure to senescent conditions leads to the enrichment of copper and iron atoms in their lower oxidation states, disrupting the iron‐thiol cluster in mitochondria and lipoic acid transferase, as well as oxidizing unsaturated fatty acids, triggering a cascade of cuproptosis and ferroptosis. Additionally, the concentration‐dependent anti‐aging effects of nanozyme is validated. Even an ultralow dose, the therapeutic can still act as a senomorphic, reducing the effects of senescence. Given its broad‐spectrum action and concentration‐adjustable anti‐aging potential, this work confirms the remarkable therapeutic capability of D‐handed PtPd2CuFe in managing atherosclerosis, a disease involving various types of senescent cells. A high‐entropy alloy (HEA) based nanozyme is employed for atherosclerosis management by integrating dual strategies involving chirality and phase engineering. This approach harnesses the tailored nanozyme's potential to function as both senolytic and senomorphic agents, thereby exerting a comprehensive anti‐senescence effect. The functional switching mechanism depends on the degree of senescence and the dosage of the nanozyme, allowing for self‐programmed action.