Mesoporous Silica‐Confined Ruthenium Nanozyme Motors Reprogram Redox‐Inflammatory Crosstalk to Suppress Atherosclerosis via NRF2 Nuclear Translocation

ABSTRACT

Elevated intravascular reactive oxygen species (ROS) and persistent inflammation are defining characteristics of the atherosclerotic microenvironment, making their simultaneous modulation a pivotal challenge in cardiovascular therapy. In response, this study presents a groundbreaking plaque microenvironment regulation strategy enabled by self‐propelled nanomotors, referred to as DDMzyme nanomotors, designed specifically for atherosclerosis treatment. These nanomotors autonomously traverse the plaque milieu, catalytically depleting excess hydrogen peroxide and superoxide anions while generating carbon monoxide, a bioactive gas that enhances the targeted accumulation of therapeutic nanoparticles. This synergistic mechanism not only reduces ROS levels during nanomotor movement but also enables additional ROS neutralization through nanozyme payloads delivered directly to the lesion. Functionally, DDMzyme treatment markedly slows atherosclerotic progression by mitigating oxidative stress and promoting cholesterol efflux from macrophages. At the molecular level, DDMzyme activates the NRF2 antioxidant defense pathway by promoting NRF2 dissociation from KEAP1, facilitating its nuclear translocation and the upregulation of downstream cytoprotective genes. This innovation marks a major advancement in precision nanomedicine, introducing a multifunctional, microenvironment‐responsive platform that concurrently targets ROS and inflammation in atherosclerosis.