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 nanozyme-based therapeutic designed to combat senescence. We start by screening ligands to optimize the synthesis of the amorphous nanozyme. By adjusting the nanozyme's composition and surface properties, we analyze its catalytic performance under both normal and aging conditions, confirming that peroxide and superoxide dismutase activity are crucial for its anti-aging therapeutic function. Subsequently, we validate the chiral-dependent therapeutic effects and demonstrate the senolytic performance of D-handed PtPd2CuFe across several aging models. Through proteomic and transcriptome analyses, we explore the mechanism underlying the senolytic action exerted by nanozyme in depth. We confirm that exposure to senescent conditions led to the enrichment of copper and iron atoms in the nanozyme's lower oxidation states, disrupting the iron-thiol cluster in mitochondria and lipoic acid transferase, as well as oxidizing unsaturated fatty acids. These actions triggered a cascade of cuproptotic and ferroptotic cell death. Additionally, we found that the nanozyme's anti-aging effects depend on concentration. Even an ultra-low dose of the therapeutic can act as a senomorphic, reducing the effects of senescence. Given its broad-spectrum action and concentration-adjustable anti-aging potential, we confirmed the remarkable therapeutic capability of D-handed PtPd2CuFe in managing atherosclerosis, a disease involving various types of senescent cells. This article is protected by copyright. All rights reserved.