Restoring immune homeostasis in atherosclerotic plaques via inorganic violet phosphorus nano-immunotherapy

Atherosclerosis is a chronic inflammatory disease driven by immune cell interactions within plaques. Nanotherapeutics targeting immune regulation offer potential for atherosclerosis treatment. However, current nanotherapies mainly focus on modulating individual immune subsets and rarely examine cross-cell anti-atherosclerotic mechanisms. Here, we develop an inorganic nanoparticle platform (PEGylated violet phosphorus nanosheets [VPNS@P]) that efficiently accumulates in the immune microenvironment of atherosclerotic plaques, particularly in macrophages and monocytes and partly T/B cells, with minimal off-target uptake. The VPNS@P platform substantially reduces plaque areas and improves plaque stability in atherosclerotic mice without observed side effects. Importantly, we unravel the underlying mechanisms of VPNS@P in atherosclerosis treatment through single-cell RNA sequencing (scRNA-seq) and experimental verification to suppress inflammation and enhance immunity, demonstrating that it effectively modulates four key immune cell populations within plaques. Additionally, VPNS@P reshapes intercellular communication among immune cells, revealing therapeutic targets for atherosclerosis. This study reveals an immune-modulating nanotherapy for atherosclerosis, highlighting the potential in treating inflammatory diseases.