Catalytic lactate-regulatory nanosystems attenuate cellular senescence for atherosclerosis amelioration.

Abstract

Endothelial senescence is a pivotal driver in the pathogenesis of atherosclerosis (AS), a process accompanied by metabolic reprogramming and increased lactate (LA) production. The accumulated LA stimulates reactive oxygen species (ROS) generation and the senescence-associated secretory phenotype, establishing a self-perpetuating inflammation-senescence feedback loop that accelerates disease progression. Therefore, depleting LA to inhibit cellular senescence represents a promising therapeutic strategy against AS. Here, we successfully fabricated a two-dimensional multi-enzyme-mimicking nanozyme (SnSe@TC MEM-nanozyme) by incorporating tannic acid-cerium (TA-Ce) frameworks onto the surface of SnSe nanozyme. Leveraging the anti-inflammatory/antioxidative properties of TA-Ce, the SnSe@TC MEM-nanozyme effectively alleviates oxidative stress and protects intracellular DNA from ROS damage. Endowed with lactate dehydrogenase-like activity, SnSe nanozyme converts LA to pyruvate, synergistically exerting anti-inflammatory and anti-senescence effects in endothelial cells while blocking endothelial-mesenchymal transition and restoring endothelial barrier function. <i>In vitro</i> and <i>in vivo</i> results confirm that the combination of anti-inflammatory/antioxidant therapy and modulation of LA levels effectively reduces plaque size and alleviates its pro-inflammatory environment. This study presents a pathology-targeted SnSe@TC MEM-nanozyme for treating AS, proposing a new paradigm of SnSe-based therapeutics for other age-related diseases.