Nature-inspired confined cascade enzyme nanoreactors for targeted atherosclerosis therapy

Oxidative stress and excessive inflammatory responses are major drivers of atherosclerosis (AS) formation and progression. In this study, we report a nature-inspired nanoreactor (named USPB@SeDMSN@NM) with superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) multienzymatic activities for targeted atherosclerosis therapy. The confined cascade nanocatalyst (USPB@SeDMSN) is designed by assembling ultrasmall Prussian blue nanoparticles (USPB NPs, SOD and CAT mimics) into the large pores of selenium (Se)-doped dendritic mesoporous silica nanoparticles (SeDMSNs, GPx mimics). The DMSN provides abundant immobilization sites for USPB NPs and Se to sequentially scavenge reactive oxygen species (ROS) in a cascade manner and forms confined reaction environments to significantly increase the local concentration of substrates and overall catalysis efficiency, which is inspired by multienzyme complexes (MECs) in nature. The neutrophil membrane was coated onto USPB@SeDMSN to endow the nanoplatforms with the ability to target atherosclerotic plaques. In vitro and in vivo results demonstrated that this nature-inspired enzyme cascade nanoreactor efficiently mitigated inflammation in macrophages and endothelial cells by scavenging various radicals and inhibited foam cell formation by reducing lipid accumulation in macrophages. Moreover, it has significant antiaging effects, protecting DNA from oxidative damage and slowing the onset of cell senescence. By conducting confined SOD-CAT/GPx cascade reactions for high-efficiency plaque microenvironment modulation, the USPB@SeDMSN@NM nanoreactor offers a powerful modality for targeted atherosclerosis therapy. This work highlights the potential of this biomimetic confined nanoreactor with cascaded multienzyme-like activities as an antioxidant and antisenescence agent for atherosclerosis treatment.